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32,811 Abstracts & Growing Daily. Sourced from the US National Library of Medicine.


Apigenin induces programmed cell death in human breast cancer cells.

Apigenin is a low toxicity and non-mutagenic phytopolyphenol and protein kinase inhibitor. It exhibits anti-proliferating effects on human breast cancer cells. Here we examined several human breast cancer cell lines having different levels of HER2/neu expression and found that apigenin exhibited potent growth-inhibitory activity in HER2/neu-overexpressing breast cancer cells but was much less effective for those cells expressing basal levels of HER2/neu. Induction of apoptosis was also observed in HER2/neu-overexpressing breast cancer cells in a dose- and time-dependent manner. However, the one or more molecular mechanisms of apigenin-induced apoptosis in HER2/neu-overexpressing breast cancer cells remained to be elucidated. A cell survival pathway involving phosphatidylinositol 3-kinase (PI3K), and Akt is known to play an important role in inhibiting apoptosis in response to HER2/neu-overexpressing breast cancer cells, which prompted us to investigate whether this pathway plays a role in apigenin-induced apoptosis in HER2/neu-overexpressing breast cancer cells. Our results showed that apigenin inhibits Akt function in tumor cells in a complex manner. First, apigenin directly inhibited the PI3K activity while indirectly inhibiting the Akt kinase activity. Second, inhibition of HER2/neu autophosphorylation and transphosphorylation resulting from depleting HER2/neu protein in vivo was also observed. In addition, apigenin inhibited Akt kinase activity by preventing the docking of PI3K to HER2/HER3 heterodimers. Therefore, we proposed that apigenin-induced cellular effects result from loss of HER2/neu and HER3 expression with subsequent inactivation of PI3K and AKT in cells that are dependent on this pathway for cell proliferation and inhibition of apoptosis. This implies that the inhibition of the HER2/HER3 heterodimer function provided an especially effective strategy for blocking the HER2/neu-mediated transformation of breast cancer cells. Our results also demonstrated that apigenin dissociated the complex of HER2/neu and GRP94 that preceded the depletion of HER2/neu. Apigenin-induced degradation of mature HER2/neu involves polyubiquitination of HER2/neu and subsequent hydrolysis by the proteasome.

J Biol Chem. 2004 Feb 6;279(6):4479-89. Epub 2003 Nov 5. PMID: 14602723


The dietary flavonoids ECGC, luteolin, quercetin, kaempferol, apigenin, and taxifolin inhibit cancer cell lipogenesis.

The consumption of food products containing high amounts of flavonoids has been reported to lower the risk of various cancers. The mechanisms underlying the cancer-protective effects of these naturally occurring polyphenolic compounds, however, remain elusive. Based on our previous finding that the cytotoxic effect of the flavanol epigallocatechin-3-gallate on prostate cancer cells correlates with its ability to inhibit fatty acid synthase (FAS, a key lipogenic enzyme overexpressed in many human cancers), we examined the anti-lipogenic effects of a panel of 18 naturally occurring polyphenolic compounds. In addition to epigallocatechin-3-gallate, five other flavonoids, more particularly luteolin, quercetin, kaempferol, apigenin, and taxifolin, also markedly inhibited cancer cell lipogenesis. Interestingly, in both prostate and breast cancer cells, a remarkable dose-response parallelism was observed between flavonoid-induced inhibition of fatty acid synthesis, inhibition of cell growth, and induction of apoptosis. In support for a role of fatty acid synthesis in these effects, the addition of exogenous palmitate, the end product of FAS, markedly suppressed the cytotoxic effects of flavonoids. Taken together, these findings indicate that the potential of flavonoids to induce apoptosis in cancer cells is strongly associated with their FAS inhibitory properties, thereby providing a new mechanism by which polyphenolic compounds may exert their cancer-preventive and antineoplastic effects.

J Biol Chem. 2005 Feb 18;280(7):5636-45. Epub 2004 Nov 8. PMID: 15533929


EGCG is a potent natural inhibitor of fatty acid synthase in intact cells and selectively induces apoptosis in prostate cancer cells.

Chemical inhibitors of fatty acid synthase (FAS) inhibit growth and induce apoptosis in several cancer cell lines in vitro and in tumor xenografts in vivo. Recently the green tea component epigallocatechin-3-gallate (EGCG) was shown to act as a natural inhibitor of FAS in chicken liver extracts. Here we investigated whether EGCG inhibits FAS activity in cultured prostate cancer cells and how this inhibition affects endogenous lipid synthesis, cell proliferation and cell viability. The high levels of FAS activity in LNCaP cells were dose-dependently inhibited by EGCG and this inhibition was paralleled by decreased endogenous lipid synthesis, inhibition of cell growth and induction of apoptosis. In contrast, epicatechin (EC), another closely related green tea polyphenolic compound, which does not inhibit FAS, had no effect on LNCaP cell growth or viability. Treatment of nonmalignant cells with low levels of FAS activity (fibroblasts) with EGCG led to a decrease in growth rate but not to induction of apoptosis. These data indicate that EGCG inhibits FAS activity as efficiently as presently known synthetic inhibitors and selectively causes apoptosis in LNCaP cells but not in nontumoral fibroblasts. These findings establish EGCG as a potent natural inhibitor of FAS in intact cells and strengthen the molecular basis for the use of EGCG as a chemopreventive and therapeutic antineoplastic agent.

Cancer Immunol Immunother. 2010 Feb 6. Epub 2010 Feb 6. PMID: 12918062


EGCG inhibits growth, disrupts the cell cycle and induces programmed cell death in androgen-sensitive and androgen-insensitive human prostate cancer cells.

Prostate cancer (PCA) is the most prevalent cancer diagnosed and the second leading cause of cancer-related deaths among men in the United States. Descriptive epidemiological data suggest that androgens and environmental exposures play a key role in prostatic carcinogenesis. Since androgen action is intimately associated with proliferation and differentiation, at the time of clinical diagnosis in humans most PCA represent themselves as a mixture of androgen-sensitive and androgen-insensitive cells. Androgen-sensitive cells undergo rapid apoptosis upon androgen withdrawal. On the other hand, the androgen-insensitive cells do not undergo apoptosis upon androgen blocking, but maintain the molecular machinery of apoptosis. Thus, agents capable of inhibiting growth and/or inducing apoptosis in both androgen-sensitive and androgen-insensitive cells will be useful for the management of PCA. In the present study, we show that (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent present in green tea, imparts antiproliferative effects against both androgen-sensitive and androgen-insensitive human PCA cells, and this effect is mediated by deregulation in cell cycle and induction of apoptosis. EGCG treatment was found to result in a dose-dependent inhibition of cell growth in both androgen-insensitive DU145 and androgen-sensitive LNCaP cells. In both the cell types, EGCG treatment also resulted in a dose-dependent G(0)/G(1)-phase arrest of the cell cycle as observed by DNA cell-cycle analysis. As evident by DNA ladder assay, confocal microscopy, and flow cytometry, the treatment of both DU145 and LNCaP cells with EGCG resulted in a dose-dependent apoptosis. Western blot analysis revealed that EGCG treatment resulted in (i) a dose-dependent increase of p53 in LNCaP cells (carrying wild-type p53), but not in DU145 cells (carrying mutant p53), and (ii) induction of cyclin kinase inhibitor WAF1/p21 in both cell types. These results suggest that EGCG negatively modulates PCA cell growth, by affecting mitogenesis as well as inducing apoptosis, in cell-type-specific manner which may be mediated by WAF1/p21-caused G(0)/G(1)-phase cell-cycle arrest, irrespective of the androgen association or p53 status of the cells.

Toxicol Appl Pharmacol. 2000 Apr 1;164(1):82-90. PMID: 10739747


Extra-virgin olive oil polyphenols may inhibit breast cancer through interfering with fatty acid synthesis.

Inhibitors of fatty acid synthase (FASN), a key enzyme involved in the anabolic conversion of dietary carbohydrates to fat in mammals, are receiving increasingly more attention as they may provide therapeutic moieties for the treatment of human malignancies. Natural compounds, such as the green tea polyphenol epigallocatechin-3-gallate, have been shown to induce anti-cancer effects by suppressing FASN, which may account for the epidemiologically observed inverse correlation between green-tea drinking and cancer risk in Oriental populations. Since extra-virgin olive oil (EVOO)-derived phenolics have been suggested to possess biological activities that may explain the health-promoting effects of the 'Mediterranean diet', we evaluated their effects on the expression of FASN protein in human breast epithelial cell lines. First, we developed a reverse phase protein microspot array (RPPA) capable of rapidly assessing the relative amount of FASN protein in whole lysates from cultured human cells. Then we tested the effects of phenolic fractions from EVOO and its main constituents including single phenols (i.e. tyrosol, hydroxytyrosol, vanillin), phenolic acids (i.e. caffeic acid, p-coumaric acid, vanillic acid, ferulic acid, elenolic acid), lignans (i.e. 1-[+]-pinoresinol, 1-[+]-acetoxy-pinoresinol), flavonoids (i.e. apigenin, luteolin), or secoiridoids (i.e. deacetoxyoleuropein aglycone, ligstroside aglycone, oleuropein glycoside, oleuropein aglycone) on FASN protein expression. EVOO polyphenols lignans, flavonoids and secoiridoids were found to drastically suppress FASN protein expression in HER2 gene-amplified SKBR3 breast cancer cells. Equivalent results were observed in MCF-7 cells engineered to overexpress the HER2 tyrosine kinase receptor, a well-characterized up-regulator of FASN expression in aggressive sub-types of cancer cells. EVOO-derived lignans, flavonoids and secoiridoids were significantly more effective than the mono-HER2 inhibitor trastuzumab ( approximately 50% reduction) and as effective as the dual HER1/HER2 tyrosine kinase inhibitor lapatinib (>or =95% reduction) at suppressing high-levels of FASN protein in HER2-overexpressing SKBR3 and MCF-7/HER2 cells. EVOO single phenols and phenolic acids failed to modulate FASN expression in SKBR3 and MCF-7/HER2 cells. These findings reveal for the first time that phenolic fractions, directly extracted from EVOO, may induce anti-cancer effects by suppressing the expression of the lipogenic enzyme FASN in HER2-overexpressing breast carcinoma cells, thus offering a previously unrecognized mechanism for EVOO-related cancer preventive effects.

Clin Nutr. 2009 Feb;28(1):34-8. Epub 2008 Nov 29. PMID: 18813848


Diosmetin inhibits cell cycle progression and proliferation in breast cancer cells.

Flavonoids constitute a large class of polyphenolic compounds with cancer preventative properties. We have examined the ability of the natural flavone diosmetin to inhibit proliferation of breast adenocarcinoma MDA-MB 468 and normal breast MCF-10A cells and found that this compound is selective for the cancer cells with slight toxicity in the normal breast cells. Diosmetin was metabolised to the structurally similar flavone luteolin in MDA-MB 468 cells, whereas no metabolism was seen in MCF-10A cells. Diosmetin caused G1 arrest at 10 microM in MDA-MB 468 cells after 48-h treatment whereas this effect was not observed in MCF-10A cells. We suggest that diosmetin exerts cytostatic effects in MDA-MB 468 cells, due to CYP1A1 and CYP1B1 catalyzed conversion to the flavone luteolin.

Oncol Rep. 2009 Jun;21(6):1525-8. PMID: 19424633


Luteolin encourages programmed cell death in lung cancer cells.

Nuclear factor kappaB (NF-kappaB) activated by tumor necrosis factor (TNF) attenuates the TNF-induced apoptosis pathway. Therefore, blockage of NF-kappaB should improve the anticancer activity of TNF. Luteolin, a naturally occurring polyphenol flavonoid, has been reported to sensitize colorectal cancer cells to TNF-induced apoptosis through suppression of NF-kappaB; however, the mechanisms of this effect have not been well elucidated. In this article, we provide evidence showing a critical role of reactive oxygen species (ROS) accumulation induced by luteolin in modulating TNF-activated pathways in lung cancer cells. Luteolin effectively suppressed NF-kappaB, whereas it potentiated the c-Jun N-terminal kinase (JNK) to increase apoptosis induced by TNF in lung cancer cells. Our results further demonstrate that luteolin induced an early phase ROS accumulation via suppression of the cellular superoxide dismutase activity. It is noteworthy that suppression of ROS accumulation by ROS scavengers butylated hydroxyanisole, and N-acetyl-L-cysteine prevented the luteolin-induced suppression of NF-kappaB and potentiation of JNK and significantly suppressed the synergistic cytotoxicity seen with cotreatment of luteolin and TNF. Taken together, these results suggest that the accumulation of ROS induced by luteolin plays a pivotal role in suppression of NF-kappaB and potentiation of JNK to sensitize lung cancer cells to undergo TNF-induced apoptosis.

Mol Pharmacol. 2007 May;71(5):1381-8. Epub 2007 Feb 12. PMID: 17296806


Oleuropein and hydroxytyrosol, two polyphenols contianed within extra-virgin olive oil, inhibit MCF-7 breast cancer cell proliferation.

The growth of many breast tumors is stimulated by estradiol (E2), which activates a classic mechanism of regulation of gene expression and signal transduction pathways inducing cell proliferation. Polyphenols of natural origin with chemical similarity to estrogen have been shown to interfere with tumor cell proliferation. The aim of this study was to investigate whether hydroxytyrosol (HT) and oleuropein (OL), two polyphenols contained in extra-virgin olive oil, can affect breast cancer cell proliferation interfering with E2-induced molecular mechanisms. Both HT and OL inhibited proliferation of MCF-7 breast cancer cells. Luciferase gene reporter experiments, using a construct containing estrogen responsive elements able to bind estrogen receptor alpha (ERalpha) and the study of the effects of HT or OL on ERalpha expression, demonstrated that HT and OL are not involved in ERalpha-mediated regulation of gene expression. However, further experiments pointed out that both OL and HT determined a clear inhibition of E2-dependent activation of extracellular regulated kinase1/2 belonging to the mitogen activating protein kinase family. Our study demonstrated that HT and OL can have a chemo-preventive role in breast cancer cell proliferation through the inhibition of estrogen-dependent rapid signals involved in uncontrolled tumor cell growth.

Mol Nutr Food Res. 2009 Dec 10. PMID: 20013881


Gicomo Castelvetro's philosophy of nutrition, e.g. (i.e., "raw vegetables... plenty of generous (olive) oil"), may be protect women against breast cancer.

We are accumulating evidence to suggest that 17(th) century Renaissance foodways -largely based on the old "Mediterranean dietary traditions"- may provide new nutraceutical management strategies against HER2-positive breast cancer disease in the 21st century. Epidemiological and experimental studies begin to support the notion that "The Sacred Law of Salads" (i.e., "raw vegetables... plenty of generous (olive) oil") -originally proposed in 1614 by Giacomo Castelvetro in its book The Fruit, Herbs&Vegetables of Italy- might be considered the first (unintended) example of customised diets for breast cancer prevention based on individual genetic make-up (i.e., nutraceuticals against human breast carcinomas bearing HER2 oncogene amplification/overexpression). First, the so-called salad vegetables dietary pattern (i.e., a high consumption of raw vegetables and olive oil) appears to exert a protective effect mostly confined to the HER2-positive breast cancer subtype, with no significant influence on the occurrence of HER2-negative breast cancers. Second, all the main olive oil constituents (i.e., the omega-9 monounsaturated fatty acid oleic acid and polyphenolic compounds such as the secoiridoid oleuropein or the lignan 1-[+]-acetoxypinoresinol) dramatically reduce HER2 expression and specifically induce apoptotic cell death in cultured HER2- positive breast cancer cells, with marginal effects against HER2-negative cells. Third, an olive oil-rich diet negatively influences experimental mammary tumorigenesis in rats likewise decreasing HER2 expression levels. If early 1600s Castelvetro's salads can be used as dietary protocols capable to protecting women against biologically aggressive HER2-positive breast cancer subtypes is an intriguing prospect that warrants to be evaluated in human pilot studies in the future. Here, at least, we would like to recognise Giacomo Castelvetro as the father of modern nutritional genomics in oncology.

Clin Transl Oncol. 2008 Jan;10(1):30-4. PMID: 18208790


Oleuropein profoundly increases the susceptibility of breast cancer cells to trastuzumab treatment.

BACKGROUND: A low incidence of breast cancer in the Mediterranean basin suggests that a high consumption of Extra Virgin Olive Oil (EVOO) might confer this benefit. While the anti-HER2 oncogene effects of the main omega-9 fatty acid present in EVOO triacylglycerols (i.e., oleic acid) have been recently described, the anti-breast cancer activities of EVOO non-glyceridic constituents--which consist of at least 30 phenolic compounds--remained to be evaluated. METHODS: Semi-preparative HPLC was used to isolate EVOO polyphenols (i.e., tyrosol, hydroxytyrosol, oleuropein). Both the anti-proliferative and the pro-apoptotic effects of EVOO phenolics were evaluated by using MTT-based quantification of metabolically viable cells and ELISA-based detection of histone-associated DNA fragments, respectively. The nature of the interaction between oleuropein aglycone and the anti-HER2 monoclonal antibody trastuzumab (Herceptin) was mathematically evaluated by the dose-oriented isobologram technique. HER2-specific ELISAs were employed to quantitatively assess both the basal cleavage of the HER2 extracellular domain (ECD) and the expression level of total HER2. The activation status of HER2 was evaluated by immunoblotting procedures using a monoclonal antibody specifically recognizing the tyrosine phosphorylated (Phosphor-Tyr1248) form of HER2. RESULTS: Among EVOO polyphenols tested, oleuropein aglycone was the most potent EVOO phenolic in decreasing breast cancer cell viability. HER2 gene-amplified SKBR3 cells were ~5-times more sensitive to oleuropein aglycone than HER2-negative MCF-7 cells. Retroviral infection of the HER2 oncogene in MCF-7 cells resulted in a "SKBR3-assimilated" phenotype of hypersensitivity to oleuropein aglycone. An up to 50-fold increase in the efficacy of trastuzumab occurred in the presence of oleuropein aglycone. A preclinical model of acquired autoresistance to trastuzumab (SKBR3/Tzb100 cells) completely recovered trastuzumab sensitivity (>1,000-fold sensitization) when co-cultured in the presence of oleuropein aglycone. Indeed, the nature of the interaction between oleuropein aglycone and trastuzumab was found to be strongly synergistic in Tzb-resistant SKBR3/Tzb100 cells. Mechanistically, oleuropein aglycone treatment significantly reduced HER2 ECD cleavage and subsequent HER2 auto-phosphorylation, while it dramatically enhanced Tzb-induced down-regulation of HER2 expression. CONCLUSION: Olive oil's bitter principle (i.e., oleuropein aglycone) is among the first examples of how selected nutrients from an EVOO-rich "Mediterranean diet" directly regulate HER2-driven breast cancer disease.

BMC Cancer. 2007;7:80. Epub 2007 May 9. PMID: 17490486


Olive oil polyphenols inhibit human colon cancer cell proliferation.

We investigated the anti-proliferative effects of an olive oil polyphenolic extract on human colon adenocarcinoma cells. Analysis indicated that the extract contained hydroxytyrosol, tyrosol and the various secoiridoid derivatives, including oleuropein. This extract exerted a strong inhibitory effect on cancer cell proliferation, which was linked to the induction of a G2/M phase cell cycle block. Following treatment with the extract (50 microg/ml) the number of cells in the G2/M phase increased to 51.82+/-2.69% relative to control cells (15.1+/-2.5%). This G2/M block was mediated by the ability of olive oil polyphenols (50 microg/ml) to exert rapid inhibition of p38 (38.7+/-4.7%) and CREB (28.6+/-5.5%) phosphorylation which led to a downstream reduction in COX-2 expression (56.9+/-9.3%). Our data suggest that olive oil polyphenols may exert chemopreventative effects in the large intestine by interacting with signalling pathways responsible for colorectal cancer development.

Biochem Biophys Res Commun. 2007 Oct 26;362(3):606-11. Epub 2007 Aug 17. PMID: 17727817


Curcumin induces programmed cell death in Leishmania through its pro-oxidant and calcium-modulating activity.

Curcumin, a polyphenol compound, has been recognized as a promising anti-cancer drug. The purpose of the present study was to investigate the cytotoxicity of curcumin to Leishmania donovani, the causative agent for visceral leishmaniasis. Flow cytometric analysis revealed that curcumin induced cell cycle arrest at G2/M phase. Incubation of Leishmania promastigotes with curcumin caused exposure of phosphatidylserine to the outer leaflet of plasma membrane. This event is preceded by curcumin-induced formation of reactive oxygen species (ROS) and elevation of cytosolic calcium through the release of calcium ions from intracellular stores as well as by influx of extracellular calcium. Elevation of cytosolic calcium is responsible for depolarization of mitochondrial membrane potential (DeltaPsim), release of Cytochrome c into the cytosol and concomitant nuclear alterations that included deoxynucleotidyltransferase-mediated dUTP end labeling (TUNEL) and DNA fragmentation. Taken together, these data indicate that curcumin has promising antileishmanial activity that is mediated by programmed cell death and, accordingly, merits further investigation as a therapeutic option for the treatment of leishmaniasis.

Apoptosis. 2008 Jul;13(7):867-82. PMID: 18506627


EGCG sensitizes human cholangiocarcinoma cells to chemotherapy-induced programmed cell death.

BACKGROUND: Green tea polyphenols are chemopreventive in several cancer models but their use as adjunctive therapeutic agents for cancer is unknown. AIMS: Cholangiocarcinomas respond poorly to chemotherapeutic agents and our aims were to assess the utility of green tea polyphenols as adjuncts to chemotherapy for cholangiocarcinoma. MATERIALS AND METHODS: We assessed the effect of purified green tea catechins on chemotherapy-induced apoptosis in KMCH, CC-LP-1 and Mz-ChA-1 human cholangiocarcinoma cells, and on chemosensitivity of Mz-ChA-1 cell xenografts in nude mice. RESULTS: Epigallocatechin-gallate (EGCG), but not the structurally related catechin epigallocatechin, sensitized cells to apoptosis induced by gemcitabine (GEM), mitomycin C or 5-fluorouracil in vitro. Mitochondrial membrane depolarization, cytosolic cytochrome c expression and apoptosis were increased in cells incubated with EGCG and GEM compared with either agent alone. Furthermore, EGCG decreased in vivo growth and increased the sensitivity to GEM of Mz-ChA-1 cell xenografts in nude mice. CONCLUSIONS: The green tea polyphenol EGCG sensitizes human cholangiocarcinoma cells to chemotherapy-induced apoptosis and warrants evaluation as an adjunct to chemotherapy for the treatment of human cholangiocarcinoma.

Liver Int. 2009 May;29(5):670-7. Epub 2009 Feb 17. PMID: 19226332


Curcumin induces programmed cell death in chronic myeloid leukemia cells.

Curcumin (1), a natural polyphenolic compound, has shown strong antioxidant and anticancer activities. Several molecular mechanisms have been attributed to its inhibitory effects on a wide range of tumor cells. In this study, the response of the chronic myeloid leukemia cell line K562 cells to 1 is investigated. Curcumin inhibited the viability of K562 cells in a dose- and time-dependent manner. Furthermore, curcumin-induced cell death was associated with the formation of the apoptosome complex, the collapse of the mitochondrial membrane potential, and caspase-3 activation. Curcumin treatment also induced Bid cleavage and downregulated the expression of Bcl-2 protein. Surprisingly, even with these molecular features of apoptosis, we showed that 1 stimulated autophagy, which was evidenced by microtubule-associated protein light chain 3 (LC3) immunoreactivty. Curcumin also increased the protein levels of beclin 1 and membrane form LC3 (LC3-II). Autophagy inhibitor bafilomycin A1 and the pan-caspase inhibitor Z-VAD-fmk suppressed curcumin-induced K562 cell death. Overall, these results suggest that curcumin induces autophagic and apoptotic death of K562 cells. These findings suggest that both apoptotic and autophagic mechanisms contribute to the curcumin-induced K562 cell death.

J Asian Nat Prod Res. 2009 Nov;11(11):918-28. PMID: 20183254


EGCG inhibits lung cancer cell growth.

(-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit tumorigenesis and cancer cell growth in animal models. Nevertheless, the dose-response relationship of the inhibitory activity in vivo has not been systematically characterized. The present studies were conducted to address these issues, as well as the involvement of reactive oxygen species (ROS), in the inhibitory action of EGCG in vivo and in vitro. We characterized the inhibitory actions of EGCG against human lung cancer H1299 cells in culture and in xenograft tumors. The growth of tumors was dose-dependently inhibited by EGCG at doses of 0.1%, 0.3% and 0.5% in the diet. Tumor cell apoptosis and oxidative DNA damage, assessed by the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and phosphorylated histone 2A variant X (gamma-H2AX), were dose-dependently increased by EGCG treatment. However, the levels of 8-OHdG and gamma-H2AX were not changed by the EGCG treatment in host organs. In culture, the growth of viable H1299 cells was dose-dependently reduced by EGCG; the estimated IC(50) (20 muM) was much higher than the IC(50) (0.15 muM) observed in vivo. The action of EGCG was mostly abolished by the presence of superoxide dismutase (SOD) and catalase, which decompose the ROS formed in the culture medium. Treatment with EGCG also caused the generation of intracellular ROS and mitochondrial ROS. Although EGCG is generally considered to be an antioxidant, the present study demonstrates the pro-oxidative activities of EGCG in vivo and in vitro in the described experimental system.

Carcinogenesis. 2010 Feb 16. Epub 2010 Feb 16. PMID: 20159951


Resveratrol has therapeutic potential for age-associated chronic diseases.

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.

Cell Cycle. 2008 Apr 15;7(8):1020-35. Epub 2008 Feb 15. PMID: 18414053


Resveratrol may be a suitable adjuvant to radioiodide therapy in treating thyroid cancer.

BACKGROUND: Resveratrol, a polyphenol found in grapes, exhibits several beneficial health effects by its antioxidant, antiinflammatory, and chemopreventive properties. The aim of the present study was to determine the effect of resveratrol on iodide trapping and efflux as well as its mode of action using FRTL-5 cells, having in mind the pivotal role of the natrium iodide symporter (NIS) in the treatment of differentiated thyroid cancers. METHODS: Cells were treated with resveratrol for various times and doses, in the presence or absence of thyrotropin (TSH). Iodide trapping, iodide efflux, rat NIS (rNIS) protein expression, and cyclic AMP (cAMP) production were evaluated. RESULTS: Resveratrol increased iodide trapping in a time-dependent (optimal 6 hours) and dose-dependent (100 microM) way in the presence of TSH. It showed an additive effect when concomitantly added with an optimal dose of TSH. Resveratrol (50 microM) increased (threefold) rNIS protein expression. In TSH-deprived cells, resveratrol also provoked an increase in rNIS protein (>3-fold in 6 hours) with an optimum at 40 microM. Resveratrol did not inhibit iodide efflux from FRTL-5 cells. It neither increased intracellular cAMP nor induced the arborization of living cells, two TSH-induced effects. A non-cAMP mode of action is highly suspected. CONCLUSIONS: Resveratrol increases iodide trapping in FRTL-5 cells, increasing iodide influx and rNIS protein level even in the absence of TSH. It has an additive effect with TSH. Consequently, resveratrol could be a promising molecule for radioiodide therapy in follicular and papillary differentiated thyroid carcinoma in association with recombinant human TSH.

Thyroid. 2010 Feb;20(2):195-203. PMID: 20151827


Theaflavins from black tea selectively inhibit SV40-transformed cancer cells.

Theaflavin (TF-1), theaflavin-3-monogallate and theaflavin-3'-monogallate mixture (TF-2), and theaflavin-3,3'-digallate (TF-3) are the major black tea polyphenols. Here we compared the effects of these polyphenols on cell growth, apoptosis, and gene expression in normal and cancerous cells. We showed that TF-2 (10-50 microM) inhibited the growth of SV40 transformed WI38 human cells (WI38VA) and Caco-2 colon cancer cells but had little effect on the growth of their normal counterparts. The IC50s of TF-2 for the growth inhibition of WI38 and WI38VA cells were, respectively, 300 and 3 microM. The other two black tea polyphenols, TF-1 and TF-3, did not exhibit such differential growth-inhibitory effect. TF-2, but not TF-1 or TF-3, induced apoptosis in transformed WI38VA cells but not in normal WI38 cells, suggesting that apoptosis was responsible, at least in part, for the differential growth-inhibitory effect of TF-2. Cox-2 has been implicated in intestinal carcinogenesis. Among the tea polyphenols tested, TF-2 and, to a lesser degree, (-)-epigallocatechin gallate inhibited cyclooxygenase (Cox)-2 gene expression. TF-2 at 50 microM completely blocked the serum-induced Cox-2 gene expression at both mRNA and protein level. Other genes, including c-fos, c-myc, thymidine kinase, proliferating cell nuclear antigen, BRCA1, BRCA2, and Cox-1, were not significantly affected by TF-2. These findings suggest that TF-2 may be responsible, at least in part, for the chemopreventive activity in black tea extracts.

Cancer Res. 2000 Nov 15;60(22):6465-71. PMID: 11103814


Green tea polyphenols reduce skin tumor cell survival.

The polycomb group (PcG) proteins are epigenetic regulators of gene expression that enhance cell survival. This regulation is achieved via action of two multiprotein PcG complexes--PRC2 (EED) and PRC1 [B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1)]. These complexes modulate gene expression by increasing histone methylation and reducing acetylation--leading to a closed chromatin conformation. Activity of these proteins is associated with increased cell proliferation and survival. We show increased expression of key PcG proteins in immortalized keratinocytes and skin cancer cell lines. We examine the role of two key PcG proteins, Bmi-1 and enhancer of zeste homolog 2 (Ezh2), and the impact of the active agent in green tea, (-)-epigallocatechin-3-gallate (EGCG), on the function of these regulators. EGCG treatment of SCC-13 cells reduces Bmi-1 and Ezh2 level and this is associated with reduced cell survival. The reduction in survival is associated with a global reduction in histone H3 lysine 27 trimethylation, a hallmark of PRC2 complex action. This change in PcG protein expression is associated with reduced expression of key proteins that enhance progression through the cell cycle [cyclin-dependent kinase (cdk)1, cdk2, cdk4, cyclin D1, cyclin E, cyclin A and cyclin B1] and increased expression of proteins that inhibit cell cycle progression (p21 and p27). Apoptosis is also enhanced, as evidenced by increased caspase 9, 8 and 3 cleavage and increased poly(adenosine diphosphate ribose) polymerase cleavage. EGCG treatment also increases Bax and suppresses Bcl-xL expression. Vector-mediated enhanced Bmi-1 expression reverses these EGCG-dependent changes. These findings suggest that green tea polyphenols reduce skin tumor cell survival by influencing PcG-mediated epigenetic regulatory mechanisms.

Carcinogenesis. 2010 Mar;31(3):496-503. Epub 2009 Dec 16. PMID: 20015867


Edible seaweed has antixoidant and antiproliferative activity against cervical cancer cell lines.

Dietary Laminaria and Porphyra sp. have been reported to reduce the risk of intestinal or mammary cancer in animal studies. Algal anticarcinogenicity may involve effects on cell proliferation and antioxidant activity. Thus, in the present study, we evaluated the effect of red alga, dulse (Palmaria palmata) and three kelp (Laminaria setchellii, Macrocystis integrifolia, Nereocystis leutkeana) extracts on human cervical adenocarcinoma cell line (HeLa cells) proliferation using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The 1-butanol soluble fractions from the methanol extracts of these algae were also evaluated for reducing activity and total polyphenol content. After 72 h incubation, HeLa cell proliferation was inhibited (pM. integrifolia>L. setchellii>N. leutkeana; and total polyphenol contents were: P. palmata>M. integrifolia=N. leutkeana>L. setchellii. The antiproliferative efficacy of these algal extracts were positively correlated with the total polyphenol contents (p

Food Chem Toxicol. 2006 Jul;44(7):1144-50. Epub 2006 Mar 22. PMID: 16554116


Rambutan and coconut peel have significant antioxidant and antiproliferative activities.

The aim of this study was to evaluate antioxidant activity and cytotoxicity against human cell lines of fruit peel extracts from rambutan, mangosteen and coconut. The highest antioxidant activity was found from rambutan peel crude extract where the highest radical scavenging capacity via ABTS assay was from its ethyl acetate fraction with a TEAC value of 23.0mM/mg and the highest ferric ion reduction activity via FRAP assay was from its methanol fraction with an EC value of 20.2mM/mg. Importantly, using both assays, these fractions had a higher antioxidant activity than butylated hydroxyl toluene and vitamin E. It was shown that the ethyl acetate fraction of rambutan peel had the highest polyphenolic content with a gallic acid equivalent of 2.3mg/mL. The results indicate that the polyphenolic compounds are responsible for the observed antioxidant activity of the extracts. Interestingly, the hexane fraction of coconut peel showed a potent cytotoxic effect on KB cell line by MTT assay (IC(50)=7.7 microg/mL), and no detectable cytotoxicity toward normal cells. We concluded that the ethyl acetate fraction of rambutan peel is a promising resource for potential novel antioxidant agents whereas the hexane fraction of coconut peel may contain novel anticancer compounds.

J Periodontol. 2009 Feb;80(2):317-23. PMID: 20510336


Wheat grass exact induces apoptosis in human cancer cells via proteasome modulation.

Natural occurring modulators of proteasome functionality are extensively investigated for their implication in cancer therapy. On the basis of our previous evidences both on proteasomal inhibition by monomeric polyphenols, and on the characterization of wheat sprout hydroalcoholic extract, herein we thoroughly report on a comparative study of the effect of wheat sprout extract on both normal and tumour cells. Treatment of isolated 20S proteasomes with wheat sprout extracts induced a gradual inhibition of all proteasome activities. Next, two wheat sprout extract components were separated: a polyphenol and a protein fraction. Both components exerted an in vitro inhibitory effect on proteasome activity. HeLa tumour cells and FHs 74 Int normal cells were exposed to both fractions, resulting in different rates of proteasome inhibition, with tumour cells showing a significantly higher degree of proteasome impairment and apoptosis induction. Furthermore, a decrease in proteasome activities and in cell survival of the human plasmacytoma RPMI 8226 cell line, upon the same treatments, was observed. Collectively, our results provide additional evidences supporting the possible use of natural extracts as coadjuvants in cancer treatments.

Pharmacopsychiatry. 1997 Jul;30(4):133-4. PMID: 19527768


Addition of whole, semiskimmed, and skimmed bovine milk reduces the total antioxidant capacity of black tea.

Epidemiological studies have shown that populations consuming fruits, vegetables, tea, cocoa, and red wine have lower incidences of cardiovascular disease, certain cancers, and eye disease. These health effects have largely been attributed to the polyphenol content of the foods and drinks studied. Black tea is rich in a range of polyphenolic compounds that could potentially have health-promoting properties. The scale of consumption of tea in the United Kingdom means that it could be an appropriate vehicle for increasing the antioxidant activity and polyphenol content of human plasma. However, it is common practice in the United Kingdom to add milk to tea, and some studies have suggested that this may decrease the overall antioxidant capacity. The objective of the present study was to analyze and compare the antioxidant capacity of 5 brands of tea and to test the hypothesis that the addition of different volumes of whole milk, semiskimmed, and skimmed milk may affect the antioxidant capacity. Each of the teas analyzed was a significant source of antioxidants. The addition of 10, 15, and 20 mL of whole, semiskimmed, and skimmed bovine milk to a 200-mL tea infusion decreased the total antioxidant capacity of all the brands of tea. Skimmed milk decreased the total antioxidant capacity of the tea infusion significantly (P

Nutr Res. 2010 Jan;30(1):14-20. PMID: 20116655


Cocoa extract reduces benzo[a]pyrene-induced mutagenicity.

Polyphenols have been shown to have potent antioxidant activity, and therefore, food containing polyphenols is expected to contribute to the prevention of cancer. However, food contains not only polyphenols but also various other constituents. We used the Ames test to investigate the effects of crude extracts of whole cacao products, which are known to be rich in polyphenols, on the mutagenicity of benzo[a]pyrene (B[a]P) in Salmonella typhimurium strain TA 98 and tert-butyl hydroperoxide (t-BuOOH) in S. typhimurium strain TA 102. B[a]P induces mutagenicity by metabolic activation and t-BuOOH induces it by generation of free radicals. While white chocolate did not modulate the numbers of revertant colonies produced by B[a]P treatment, milk chocolate and cacao powder extracts did. On the other hand, surprisingly, none of the cacao products tested affected the number of revertant colonies when t-BuOOH was used as the mutagen. At maximum concentration (13.25 mg cacao powder/ml), the crude cacao powder extract reduced ethoxyresorufin O-deethylase activity to 17.4% of the control, suggesting that whole cacao products inhibit cytochrome P450 (CYP) 1A activity. In conclusion, inhibition of CYP1A activity by cacao products may prevent DNA damage by reducing metabolic activation of carcinogens.

Phytother Res. 2009 Aug;23(8):1134-9. PMID: 19170136


Cocoa polyphenols extracts have an antiproliferative effect on prostate cancer cell growth.

Cocoa contains many different types of physiologically active components. It was shown that cocoa beans are rich in specific antioxidants such as flavonoids, catechins, epicatechins and proanthocyanidins. Additionally, beta-sitosterol, the most common phytosterol, may play a protective role in the development of cancer. The aim of this in-vitro study was to evaluate the inhibitory effect of different cocoa polyphenols extracts, alone or combined with beta-sitosterol, on two human prostate cancer cell lines (nonmetastatic 22Rv1 cells and metastatic DU145 cells) and a normal human prostate cell line (RWEP-1). A synergy between beta-sitosterol and cocoa polyphenols extract was also researched. Cells were treated independently with five products from 1 to 72 h: (1/) synthetic beta-sitosterol, (2/) a cocoa polyphenols extract supplemented with beta-sitosterol, (3/) three different cocoa polyphenols extracts naturally containing beta-sitosterol. In the experiment, beta-sitosterol was tested from 10(-6) to 10(-3)%; cocoa polyphenols extract supplementation was with 0.72% beta-sitosterol; finally cocoa polyphenols extracts were added to the cells at very low concentrations ranging from 0.001 to 0.2%. The growth and viability of cells were measured using colorimetric assay at 1, 3, 6, 24, 48 and 72 h of treatment. IC50 and IC100 corresponding to the concentration leading to a decrease of 50% and 100% of cell growth were determined. At the highest tested concentration, cocoa polyphenols extracts induced a complete inhibition of growth of metastatic and nonmetastatic cancer cell lines. In addition, cocoa polyphenols extracts were more active against local cancer cells than against metastatic cells. Moreover, at the highest tested concentration, cocoa polyphenols extracts are not effective on a normal prostate cell lines. Beta-sitosterol induced low growth inhibition of both cancer cell line. Cocoa polyphenols extracts, however, were significantly more active and showed a strong and fast inhibition of cell growth than beta-sitosterol alone. No synergy or addition was observed when beta-sitosterol was tested together with the cocoa polyphenols extract. Our results show that cocoa polyphenols extracts have an antiproliferative effect on prostate cancer cell growth but not on normal cells, at the highest tested concentration.

Am J Physiol Renal Physiol. 2007 Oct;293(4):F1256-61. Epub 2007 Aug 1. PMID: 16835506


An anthocyanin fraction from potato extracts is cytotoxic to prostate cancer cells.

Polyphenols from fruits and vegetables exhibit anticancer properties both in vitro and in vivo and specialty potatoes are an excellent source of dietary polyphenols, including phenolic acids and anthocyanins. This study investigated the effects of specialty potato phenolics and their fractions on LNCaP (androgen dependent) and PC-3 (androgen independent) prostate cancer cells. Phenolic extracts from four specialty potato cultivars CO112F2-2, PATX99P32-2, ATTX98462-3 and ATTX98491-3 and organic acid, phenolic acid and anthocyanin fractions (AF) were used in this study. CO112F2-2 cultivar extracts and their AF at 5 mug chlorogenic acid eq/ml were more active and inhibited cell proliferation and increased the cyclin-dependent kinase inhibitor p27 levels in both LNCaP and PC-3 cells. Potato extract and AF induced apoptosis in both the cells and, however, the effects were cell context dependent. Cell death pathways induced by potato extract and AF were associated with mitogen-activated protein kinase and c-jun N-terminal kinase activation and these kinases activated caspase-independent apoptosis through nuclear translocation of endonuclease G (Endo G) and apoptosis-inducing factor in both cell lines. Induction of caspase-dependent apoptosis was also kinase dependent but was observed only in LNCaP cells. Kinase inhibitors reversed this nuclear translocation of endonuclease G and apoptosis-inducing factor. This is the first report showing that the cytotoxic activities of potato extract/AF in cancer cells were due to activation of caspase-independent apoptosis. Current studies are focused on identifying individual components of the AF responsible for the induction of cell death pathways in prostate and other cancer cell lines and developing potato cultivars that overexpress these active compounds.

Carcinogenesis. 2007 Oct;28(10):2227-35. Epub 2007 May 23. PMID: 17522067


Curcumin has anti-breast cancer activity.

Since curcumin, a polyphenol extracted from the rhizomes of Curcuma longa L. (Zingiberaceae), has been proposed for breast cancer chemoprevention, the aim of the present work was to determine if it had anti-tumour effects on mammary cells which are resistant to oxidative damage. ZR-75-1 cells were treated with curcumin and copper(II) sulphate in order to evaluate cell death and gamma-glutamyltranspeptidase (GGTP) activity. Curcumin was cytotoxic in a dose-dependent manner (loss of viability with lactate-dehydrogenase release) with apoptotic effects on ZR-75-1 cells. Also, curcumin displayed an antioxidant effect only on the copper-oxidized cells. The GGTP activity was decreased in a dose-dependent manner by curcumin, with the changes in this parameter accounting for neoplastic inhibition (direct relation between the enzyme activity and cellular viability). Summing up, our results suggest that curcumin induced apoptosis in ZR-75-1 with an antioxidant activity performed on those treated with copper(II) sulphate, which should be explored more thoroughly with the involvement of the GGTP enzyme activity as biomarker of their malignancy.

J Exp Ther Oncol. 2010;8(3):261-6. PMID: 20734924


Coffee may exert its chemopreventive properties through metabolism and detoxification of xenobiotics.

Enzymes of xenobiotic metabolism are involved in the activation and detoxification of carcinogens and can play a pivotal role in the susceptibility of individuals toward chemically induced cancer. Differences in such susceptibility are often related to genetically predetermined enzyme polymorphisms but may also be caused by enzyme induction or inhibition through environmental factors or in the frame of chemopreventive intervention. In this context, coffee consumption, as an important lifestyle factor, has been under thorough investigation. Whereas the data on a potential procarcinogenic effect in some organs remained inconclusive, epidemiology has clearly revealed coffee drinkers to be at a lower risk of developing cancers of the colon and the liver and possibly of several other organs. The underlying mechanisms of such chemoprotection, modifications of xenobiotic metabolism in particular, were further investigated in rodent and in vitro models, as a result of which several individual chemoprotectants out of the>1000 constituents of coffee were identified as well as some strongly metabolized individual carcinogens against which they specifically protected. This chapter discusses the chemoprotective effects of several coffee components and whole coffee in association with modifications of the usually protective glutathione-S-transferase (GST) and the more ambivalent N-acetyltransferase (NAT). A key role is played by kahweol and cafestol (K/C), two diterpenic constituents of the unfiltered beverage that were found to reduce mutagenesis/tumorigenesis by strongly metabolized compounds, such as 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine, 7,12-dimethylbenz[a]anthracene, and aflatoxin B(1), and to cause various modifications of xenobiotic metabolism that were overwhelmingly beneficial, including induction of GST and inhibition of NAT. Other coffee components such as polyphenols and K/C-free coffee are also capable of increasing GST and partially of inhibiting NAT, although to a somewhat lesser extent.

Methods Enzymol. 2005;401:307-41. PMID: 16399395


Oats contain more than 20 unique polyphenols with strong antioxidant activity.

Oats are known to be a healthy food for the heart due mainly to their high beta-glucan content. In addition, they contain more than 20 unique polyphenols, avenanthramides, which have shown strong antioxidant activity in vitro and in vivo. The polyphenols of oats have also recently been shown to exhibit anti-inflammatory, antiproliferative, and anti-itching activity, which may provide additional protection against coronary heart disease, colon cancer, and skin irritation.

Nutr Rev. 2009 Dec;67(12):731-5. PMID: 19941618


buckwheat extract has antioxidant and photoprotective properties.

In recent years, the incidence of skin cancer has risen remarkably. Sun light, especially the included ultraviolet (UV)-radiation, is seen as important trigger for the development of skin cancer. Thus, there is an increasing interest in the development of UV-protective substances to use them as sun care products. One approach is the topical application of herbal antioxidants. Plant-derived antioxidants are often extracts and therefore contain a complex mixture of constituents, like flavonoids and polyphenols, which contribute to the overall activity of the extract. In the present study an extract from buckwheat herb was compared to rutin, which is the main constituent of the extract, regarding their antioxidant and radical scavenging activity. Additionally, the photoprotective properties of the extract were compared to those of a commercial UV absorber. The antioxidant activity was quantified regarding the reactivity versus the 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH). The photoprotective properties of the extract were examined by the inhibition of the photosensitized lipid peroxidation of linolic acid. In the DPPH assay, the extract had significantly better antioxidant activity than pure rutin. The extract prevented more effectively the UV-induced peroxidation of linolic acid than rutin itself or the commercial UV absorber. The use of the extract from buckwheat herb seems to be more beneficial than the use of pure rutin. This can be referred to the presence of minor phenolic compounds in the extract. The results indicate that it is advisable to use antioxidants rather than only UV absorber to obtain a maximum of photo protection.

Pharmazie. 2006 Mar;61(3):237-40. PMID: 16599267


Polyphenols may reduce chemotherapy resistance in cancer cells.

TNF-related apoptosis-inducing ligand (TRAIL) and its receptors are attractive targets for anticancer therapy owing to their ability to trigger apoptosis selectively in cancer cells but not in normal cells. To date, many combinatorial strategies, such as chemotherapy or radiotherapy, have given encouraging results for overcoming TRAIL resistance in preclinical models. In this review, we provide an overview of the molecular mechanisms underlying sensitization to TRAIL-induced apoptosis by polyphenols. These naturally occurring compounds can restore tumor cell sensitivity to TRAIL-induced cell death with no apparent toxicity towards normal cells. Both extrinsic and intrinsic pathways can be modulated by polyphenols, the activation of which largely depends on the cell type, the particular polyphenolic compound, and the conditions of treatment. The large variety of polyphenol cellular targets could prove useful in circumventing TRAIL resistance. The relevance of these combined treatments for cancer therapy is discussed in the light of recent preclinical studies.

Cell Mol Life Sci. 2010 Sep;67(18):3115-30. Epub 2010 May 29. PMID: 20508968


Review: Resveratrol's therapeutic role in Alzheimer's disease.

Resveratrol, a red wine polyphenol, is known to protect against cardiovascular diseases and cancers, as well as to promote antiaging effects in numerous organisms. It also modulates pathomechanisms of debilitating neurological disorders, such as strokes, ischemia, and Huntington's disease. The role of resveratrol in Alzheimer's disease is still unclear, although some recent studies on red wine bioactive compounds suggest that resveratrol modulates multiple mechanisms of Alzheimer's disease pathology. Emerging literature indicates that mechanisms of aging and Alzheimer's disease are intricately linked and that these mechanisms can be modulated by both calorie restriction regimens and calorie restriction mimetics, the prime mediator of which is the SIRT1 protein, a human homologue of yeast silent information regulator (Sir)-2, and a member of NAD+-dependent histone deacetylases. Calorie restriction regimens and calorie restriction-mimetics trigger sirtuins in a wide variety of organisms, ranging from bacteria to mouse. In a mouse model of Huntington's disease, resveratrol-induced SIRT1 was found to protect neurons against ployQ toxicity and in Wallerian degeneration slow mice, resveratrol was found to protect the degeneration of neurons from axotomy, suggesting that resveratrol may possess therapeutic value to neuronal degeneration. This paper mainly focuses on the role of resveratrol in modulating AD pathomechanisms.

Brain Res Rev. 2006 Sep;52(2):316-26. PMID: 16766037


Rosmarinic acid encourages cell death in human leukemia cells.

Because tumor necrosis factor-alpha (TNF-alpha) is well-known to induce inflammatory responses, thus its clinical use is limited in cancer treatment. Rosmarinic acid (RA), a naturally occurring polyphenol flavonoid, has been reported to inhibit TNF-alpha-induced NF-kappaB activation in human dermal fibroblasts. However, the precise mechanisms of RA have not been well elucidated in TNF-alpha-mediated anti-cancer therapy. In this study, we found that RA treatment significantly sensitizes TNF-alpha-induced apoptosis in human leukemia U937 cells through the suppression of nuclear transcription factor-kappaB (NF-kappaB) and reactive oxygen species (ROS). Activation of caspases in response to TNF-alpha was markedly increased by RA treatment. However, pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, was capable of significantly restoring cell viability in response to combined treatment. RA also suppressed NF-kappaB activation through inhibition of phosphorylation and degradation of IkappaBalpha, and nuclear translocation of p50 and p65. This inhibition was correlated with suppression of NF-kappaB-dependent anti-apoptotic proteins (IAP-1, IAP-2, and XIAP). RA treatment also normalized TNF-alpha-induced ROS generation. Additionally, ectopic Bcl-2 expressing U937 reversed combined treatment-induced cell death, cytochrome c release into cytosol, and collapse of mitochondrial potential. These results demonstrated that RA inhibits TNF-alpha-induced ROS generation and NF-kappaB activation, and enhances TNF-alpha-induced apoptosis.

Cancer Lett. 2010 Feb 28;288(2):183-91. Epub 2009 Jul 19. PMID: 19619938


Immature plum induces programmed cell death in liver cancer cells.

In the present study, the effect of an extract of immature Prunus salicina Lindl. cv. Soldam fruit on the viability and induction of apoptosis in human hepatocellular carcinoma HepG2 cells was investigated. The results showed that in comparison with other cancer cells, the growth inhibition exerted by immature plum extracts was greatest in HepG2. Apoptosis in HepG2 cells mediated by immature plums was associated with "death receptor signaling." Immature plum extracts significantly increased the activation of caspase-8, -10, and -3 and expression of the caspase-3 target proteins alpha-fodrin (induces membrane blebbing and cell shrinkage), poly(ADP-ribose) polymerase (a nuclear enzyme that is involved in DNA repair following DNA nicks), and DNA fragmentation factor (induces apoptotic DNA fragmentation). The total yield of identified polyphenols in immature plum extract was 10 g/kg dry weight. The major components, (-)-epicatechin and (-)-gallocatechin gallate, were 34.7% and 28.6% of total polyphenols, respectively. (+)-Catechin, (-)-epicatechin gallate, and (-)-catechin gallate were also found. On the basis of these results, the immature plum (P. salicina Lindl. cv. Soldam) and its active compound, (-)-epicatechin, are expected to be a natural resource for developing novel therapeutic agents for cancer prevention and treatment.

J Med Food. 2009 Jun;12(3):518-27. PMID: 19627199


Flavanoid rich honey may act as chemosensitizers in multidrug resistant cancers.

Cancer is one of the deadly diseases that burdens the society since long-time. Although design of chemotherapy is well-advanced, still it could not prevent the cancer death by hundred percent. One of the major stumbling blocks for cancer chemotherapy is multidrug resistance (MDR) developed by cancer cells. Role of ABC family of transporter proteins is well recognized in MDR. P-glycoprotein (P-gp), member of ABC transporter family, has been described for drug resistance and a low bioavailability of drugs by pumping structurally unrelated drugs out of the cells at the cost of ATP hydrolysis. Recently various P-gp inhibitors (chemosensitizers) are studied extensively to reverse MDR. In this scenario, we propose honey with multitude of polyphenolic flavonoids as a plausible candidate for inhibiting the P-gp proteins. Common flavonoids of honey like chrysin, genistein, biochanin, quercetin, kaempferol, and naringenin have found to interact with P-gp transporters. Generally chemosensitizers bind with transmembrane domain (TMD) in the P-gp transporter but flavonoids are bi-functional in reversing the MDR. Flavonoids can inhibit the ATPases activity involved in drug efflux and also it may serve as substrates for P-gp transporters, thereby causing competitive inhibition towards other substrates. This dual-mode of flavonoids interaction with P-gp transporter enhances the therapeutic index. Hence we promulgate honey with rich flavonoid content as a potential candidate for reversing MDR. If our hypothesis is true, honey a novel chemosensitizer will reduce the huge amount invested in developing new chemosensitizers to overcome the burden of chemo-resistance.

Med Hypotheses. 2011 Jan 17. Epub 2011 Jan 17. PMID: 21247706


Red wine polyphenols cause growth inhibition and programmed cell death in acute lymphoblastic leukaemia cells.

Several epidemiological studies suggest that a diet rich in fruits and vegetables, which contain high levels of polyphenols, is associated with a reduced risk of cancer. The aim of the present study was to determine whether a red wine polyphenolic extract (RWPs, a rich source of polyphenols; 2.9g/L) affects the proliferation of human lymphoblastic leukaemia cells (Jurkat cells) and, if so, to determine the underlying mechanism. Cell proliferation and viability were determined by the MTS and trypan blue exclusion assays, respectively. Cell cycle analysis, apoptosis activity and oxidative stress levels were assessed by flow cytometry, and the expression of p73, UHRF1 and active caspase-3 by Western blot analysis. RWPs inhibited the proliferation of Jurkat cells and induced G0/G1 cell cycle arrest in a concentration-dependent manner. Moreover, RWPs triggered apoptosis, which is associated with an increased expression level of the pro-apoptotic protein p73 and the active caspase-3. RWPs induced apoptosis confirmed by DNA fragmentation analysis, and this effect was associated with down-regulation of the antiapoptotic protein UHRF1. Furthermore RWPs significantly increased the formation of reactive oxygen species (ROS). Intracellular scavengers of superoxide anions (MnTMPyP, MnTBAP, PEG-SOD) prevented the RWPs-induced formation of ROS and apoptosis, while native extracellular superoxide dismutase (SOD) was without effect. In addition, the effect of RWPs on the expression levels of p73, active caspase-3 and UHRF1 was also prevented by MnTMPyP. Thus, these findings indicate that RWPs induce apoptosis in Jurkat cells by a redox-sensitive mechanism involving the intracellular formation of superoxide anions and consequently the up-regulation of p73 and down-regulation of UHRF1.

Eur J Cancer. 2010 Mar;46(5):983-94. Epub 2010 Jan 13. PMID: 20074931


Brazillian enhances programmed cell death in prostate cancer cells.

Prostate cancer represents an ideal disease for chemopreventive intervention. Propolis possesses immuno-modulatory, anti-tumour and chemopreventive properties. The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important endogenous anti-cancer agent that induces apoptosis selectively in tumour cells. However, some cancer cells are resistant to TRAIL-mediated apoptosis. Naturally occurring phenolic and polyphenolic compounds sensitize TRAIL-resistant cancer cells and augment the apoptotic activity of TRAIL. The ethanolic extract of Brazilian green propolis (EEP) is rich in phenolic components. Our in vitro results indicate the potential targets in the TRAIL-induced apoptotic pathway for the cancer chemopreventive activity of Brazilian propolis. We examined the cytotoxic and apoptotic effects of Brazilian EEP and its bioactive components in combination with TRAIL on LNCaP prostate cancer cells.The chemical composition of Brazilian green propolis was determined by high performance liquid chromatography-diode array detection. The cytotoxicity was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl-tetrazolium and lactate dehydrogenase assays. Apoptosis was detected using annexin V-FITC by flow cytometry and fluorescence microscopy. The mitochondrial membrane potential (∆Ψm) was evaluated using DePsipher staining by fluorescence microscopy. Flow cytometry was used to analyse death receptor (TRAIL-R1 and TRAIL-R2) expression in LNCaP cells. The inhibition of nuclear factor-κB (NF-κB) (p65) activation in cancer cells was confirmed by the ELISA-based TransAM NF-κB kit. The LNCaP cells were shown to be resistant to TRAIL-induced apoptosis. Our study demonstrates that EEP sensitizes TRAIL-resistant prostate cancer cells. The main phenolic components detected in Brazilian green propolis are artepillin C, quercetin, kaempferol and p-coumaric acid. Brazilian propolis and its bioactive components markedly augmented TRAIL-mediated apoptosis and cytotoxicity in prostate cancer cells. Brazilian EEP enhanced the expression of TRAIL-R2 and the activity of NF-κB in LNCaP cells.The co-treatment of prostate cancer cells with 100 ng/ml TRAIL and 50 µg/ml EEP increased the percentage of apoptotic cells to 65.8±1.2% and caused a significant disruption of ∆Ψm in LNCaP cells. We show that Brazilian EEP helped cells overcome TRAIL resistance by engaging both intrinsic andextrinsic apoptotic pathways and regulating NF-κB activity. The data demonstrate the important role of Brazilian green propolis and its bioactive compounds in prostate cancer chemoprevention through the enhancement of TRAIL-mediated apoptosis.

Int J Oncol. 2011 Feb 1. Epub 2011 Feb 1. PMID: 21286663


Review: Curcumin has therapeutic potential in the treatment of head & neck cancers.

ABSTRACT: Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-kB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-alpha, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent.

Mol Cancer. 2011 Feb 7;10(1):12. Epub 2011 Feb 7. PMID: 21299897


Testoterone enhances curcumin's anti-prostate cancer activity.

Recently, we reported that combined ingestion of soy isoflavones and curcumin significantly decreased the serum level of prostate-specific antigen based on a randomized placebo-controlled double-blind clinical study. We investigated whether these polyphenols inhibited the proliferation of prostate cancer cells by activating a DNA damage response. The effects of isoflavones and curcumin on the expression and phosphorylation of ataxia-telangiectasia-mutated kinase (ATM), histone H2AX variant (H2AX) and checkpoint kinase2 (Chk2) were examined in LNCaP cells. The induction of apoptosis in LNCaP cells was evaluated by poly(ADP-ribose) polymerase (PARP) cleavage. Furthermore, the effects of a testosterone supplement on modulation of the DNA damage response were examined. Combined treatment of isoflavones and curcumin additively suppressed cellular proliferation and induced phosphorylation of ATM, histone H2AX, Chk2 and p53. Testosterone augmented the activation of the DNA damage response and PARP cleavage induced by curcumin. Our results indicate that activation of the DNA damage response by polyphenols might suppress the malignant transformation of prostate cancer. In addition, testosterone, when combined with curcumin, may have suppressive effects on the progression of prostate cancer. (Cancer Sci 2011; 102: 468-471).

Cancer Sci. 2011 Feb;102(2):468-71. Epub 2010 Dec 7. PMID: 21134073


Curcumin compares favorably with oxaliplatin as an antiproliferative in colorectal cell lines.

Colorectal cancer remains a leading cause of cancer death worldwide, despite markedly improved response rates to current systemic therapies. Oxaliplatin either alone or incorporated into 5-fluorouracil/leucovorin regimes has resulted in increased survival rates, particularly with regards to metastatic colorectal carcinoma. The chemopreventive polyphenol curcumin, which is currently in clinical trial, has been advocated for use in colorectal cancer either singly or in combination with chemotherapeutic drugs. In this study, the antiproliferative capacity of both compounds was compared in HCEC (normal-derived), HT29 (p53 mutant adenocarcinoma) and HCT116 (p53wt adenocarcinoma) colorectal cell lines to determine whether effects were cell-type specific at pharmacologically achievable doses, and whether the combination resulted in enhanced efficacy. Both oxaliplatin and curcumin displayed marked antiproliferative capacity at therapeutic concentrations in the two tumor cell lines. Order of sensitivity to oxaliplatin was HCT116>HT29>HCEC, whereas order of sensitivity to curcumin was HT29>HCT116>HCEC. HCT116 cells underwent induction of G2/M arrest in response to both oxaliplatin (irreversible) and curcumin (reversible). Apoptosis was induced by both agents, and up to 16-fold induction of p53 protein was observed in response to the combination. Antiproliferative effects in HT29 cells were largely cell cycle independent, and were mediated by induction of apoptosis. Effects were greatly enhanced in both cell lines when agents were combined. This study provides further evidence that curcumin may be of use in therapeutic regimes directed against colorectal cancer, and suggests that in combination with oxaliplatin it may enhance efficacy of the latter in both p53wt and p53 mutant colorectal tumors.

Int J Cancer. 2007 Jul 1;121(1):175-83. PMID: 17330230


Curcumin inhibits cholesterol uptake.

BACKGROUND: Curcumin is a polyphenol and the one of the principle curcuminoids of the spice turmeric. Its antioxidant, anti-cancer and anti-inflammatory effects have been intensively studied. Previous in vivo studies showed that administration of curcumin also decreased cholesterol levels in the blood, and the effects were considered to be related to upregulation of LDL receptor. However, since plasma cholesterol levels are also influenced by the uptake of cholesterol in the gut, which is mediated by a specific transporter Niemann-Pick Cl-like 1 (NPC1L1) protein, the present study is to investigate whether curcumin affects cholesterol uptake in the intestinal Caco-2 cells.METHODS: Caco-2 cells were cultured to confluence. The micelles composed of bile salt, monoolein, and 14C-cholesterol were prepared. We first incubated the cells with the micelles in the presence and absence of ezetimibe, the specific inhibitor of NPC1L1, to see whether the uptake of the cholesterol in the cells was mediated by NPC1L1. We then pretreated the cells with curcumin at different concentrations for 24 h followed by examination of the changes of cholesterol uptake in these curcumin-treated cells. Finally we determined whether curcumin affects the expression of NPC1L1 by both Western blot analysis and qPCR quantification.RESULTS: We found that the uptake of radioactive cholesterol in Caco-2 cells was inhibited by ezetimibe in a dose-dependent manner. The results indicate that the uptake of cholesterol in this study was mediated by NPC1L1. We then pretreated the cells with 25-100 muM curcumin for 24 h and found that such a treatment dose-dependently inhibited cholesterol uptake with 40% inhibition obtained by 100 muM curcumin. In addition, we found that the curcumin-induced inhibition of cholesterol uptake was associated with significant decrease in the levels of NPC1L1 protein and NPC1L1 mRNA, as analyzed by Western blot and qPCR, respectively.CONCLUSION: Curcumin inhibits cholesterol uptake through suppression of NPC1L1 expression in the intestinal cells.

Lipids Health Dis. 2010;9:40. Epub 2010 Apr 19. PMID: 20403165


Curcumin may facilitate chemoprevention via direct binding to, and activation of, vitamin D receptor (VDR).

The nuclear vitamin D receptor (VDR) mediates the actions of 1,25-dihydroxyvitamin D(3) (1,25D) to regulate gene transcription. Recently, the secondary bile acid, lithocholate (LCA), was recognized as a novel VDR ligand. Using reporter gene and mammalian two-hybrid systems, immunoblotting, competitive ligand displacement and quantitative real-time PCR, we identified curcumin (CM), a turmeric-derived bioactive polyphenol, as a likely additional novel ligand for VDR. CM (10(-5) M) activated transcription of a luciferase plasmid containing the distal vitamin D responsive element (VDRE) from the human CYP3A4 gene at levels comparable to 1,25D (10(-8) M) in transfected human colon cancer cells (Caco-2). While CM also activated transcription via a retinoid X receptor (RXR) responsive element, activation of the glucocorticoid receptor (GR) by CM was negligible. Competition binding assays with radiolabeled 1,25D confirmed that CM binds directly to VDR. In mammalian two-hybrid assays employing transfected Caco-2 cells, CM (10(-5) M) increased the ability of VDR to recruit its heterodimeric partner, RXR, and steroid receptor coactivator-1 (SRC-1). Real-time PCR studies revealed that CM-bound VDR can activate VDR target genes CYP3A4, CYP24, p21 and TRPV6 in Caco-2 cells. Numerous studies have shown chemoprotection by CM against intestinal cancers via a variety of mechanisms. Small intestine and colon are important VDR-expressing tissues where 1,25D has known anticancer properties that may, in part, be elicited by activation of CYP-mediated xenobiotic detoxification and/or up-regulation of the tumor suppressor p21. Our results suggest the novel hypothesis that nutritionally-derived CM facilitates chemoprevention via direct binding to, and activation of, VDR.

J Nutr Biochem. 2010 Dec;21(12):1153-61. Epub 2010 Feb 12. PMID: 20153625


Curcumin may work synergistically with taxane chemotherapy for hormone-refractory prostate cancer treatment.

Complementary and alternative therapies for neoplastic diseases treatment and prevention receive increasing attention from the medical community. Prostate cancer (PC) is the most frequently diagnosed malignancy and the second major cause of male death in industrialized countries. The chemopreventive properties and clinical safety of curcumin, a polyphenolic derivative, have already been established. However, curcumin regimen value in addition to conventional hormone refractory (HR) PC treatment remains largely unknown. This review article summarizes mechanisms by which curcumin may decrease HRPC aggressive proliferation and potentiate activity of taxane therapy. Our analysis suggests that curcumin alone has a therapeutic value in HRPC. In combination with a taxane agent, this compound may enhance cytotoxicity and retard PC cell resistance to taxane. As a consequence, a rationale is provided for considering the possible benefits of curcumin regimen in combination with taxane therapy in HRPC patients.

Nutr Cancer. 2010;62(2):148-53. PMID: 20099188


Curcumin inhibits IMP dehydrogenase, a target for anticancer and antiviral chemotherapy agents.

Inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in the de novo synthesis of guanine nucleotides, is a therapeutic target for anticancer and antiviral agents. Among the 15 different polyphenols examined, curcumin was found to have an inhibitory effect on the IMPDH activity in both a competitive and uncompetitive manner and to suppress the cellular GTP level in HT-29 colon carcinoma cells.

Biosci Biotechnol Biochem. 2010;74(1):185-7. Epub 2010 Jan 7. PMID: 20057137


Curcumin inhibits Ewing sarcoma.

Curcumin is a naturally occurring polyphenolic compound found in the turmeric, which is used as food additive in Indian cooking and as a therapeutic agent in traditional Indian medicine. Curcumin is currently under investigation as a chemotherapeutic and chemopreventive agent in adult cancer models at both pre-clinical and clinical levels. In this preliminary study, we show that curcumin is effective in causing cell cycle arrest, inducing apoptosis, and suppressing colony formation in the Ewing sarcoma cell line SK-NEP-1. Curcumin causes upregulation of cleaved caspase 3 and downregulation of phospho-Akt, producing apoptosis in Ewing sarcoma cells at an inhibitory concentration 50% (IC50) of approximately 4 μM. Our findings indicate a need for further evaluation of curcumin in chemotherapy and chemoprevention of Ewing sarcoma.

Med Oncol. 2010 Dec;27(4):1096-101. Epub 2009 Oct 27. PMID: 19859844


Curcumin inhibit human lung cancer cells.

Curcumin, a polyphenolic compound, is the active component of Curcuma longa and has been extensively investigated as an anticancer drug that modulates multiple pathways. Eukaryotic initiation factors (eIFs) have been known to play important roles in translation initiation, which controls cell growth and proliferation. Little is known about the effects of curcumin on eIFs in lung cancer. The objective of this study was to exam the curcumin cytotoxic effect and modulation of two major rate-limiting translation initiation factors, including eIF2α and eIF4E protein expression levels in lung adenocarcinoma epithelial cell line A549. Cytotoxicity was measured by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and protein changes were determined by Western blot. A549 cells were treated with 0-240 μM curcumin for 4-96h. The inhibitory effects of curcumin on cytotoxicity were dose- and time-dependent (P

Mol Biol Rep. 2010 Oct;37(7):3105-10. Epub 2009 Oct 15. PMID: 19826913


Review: Curcumin may be an ideal anti-cancer therapy due to is role in positively modulating the machineries of cell survival, proliferation, invasion, and angiogenesis.

Although safe in most cases, ancient treatments are ignored because neither their active components nor their molecular targets are well defined. This is not the case, however, with curcumin, a yellow-pigment substance and component of turmeric (Curcuma longa), which was identified more than a century ago. Recently, extensive research has addressed the chemotherapeutic potential of this relatively nontoxic-plant-derived polyphenol. Because most cancers are caused by deregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. In this regard, curcumin has been reported to have immense potentiality for being used in cancer chemotherapy because of its control over the machineries of cell survival, proliferation, invasion, and angiogenesis. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. This review seeks to summarize the unique multifocal signal modulatory properties of the "ancient weapon," curcumin, which may be exploited for successful clinical cancer prevention.

Mol Cell Biochem. 2010 Mar;336(1-2):85-95. Epub 2009 Oct 14. PMID: 19826768


Curcumin may block brain tumor formation.

Turmeric, an essential ingredient of culinary preparations of southeast Asia, contains a major polyphenolic compound, named curcumin or diferuloylmethane, which eliminates cancer cells derived from a variety of peripheral tissues. Although in vitro experiments have addressed its anti-tumor property, no in vivo studies have explored its anti-cancer activity in the brain. Oral delivery of this food component has been less effective because of its low solubility in water. We show that a soluble formulation of curcumin crosses the blood-brain barrier but does not suppress normal brain cell viability. Furthermore, tail vein injection, or more effectively, intracerebral injection through a cannula, blocks brain tumor formation in mice that had already received an intracerebral bolus of mouse melanoma cells (B16F10). While exploring the mechanism of its action in vitro we observed that the solubilized curcumin causes activation of proapoptotic enzymes caspase 3/7 in human oligodendroglioma (HOG) and lung carcinoma (A549) cells, and mouse tumor cells N18 (neuroblastoma), GL261 (glioma), and B16F10. A simultaneous decrease in cell viability is also revealed by MTT [3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide] assays. Further examination of the B16F10 cells showed that curcumin effectively suppresses Cyclin D1, P-NF-kB, Bcl(XL), P-Akt, and VEGF, which explains its efficacy in blocking proliferation, survival, and invasion of the B16F10 cells in the brain. Taken together, solubilized curcumin effectively blocks brain tumor formation and also eliminates brain tumor cells. Therefore, judicious application of such injectable formulations of curcumin could be developed into a safe therapeutic strategy for treating brain tumors.

Brain Res. 2009 Feb 10. Epub 2009 Feb 10. PMID: 19368804


Curcumin inhibits integrin (alpha6beta4)-dependent breast cancer cell motility and invasion.

Curcumin, a polyphenol natural product isolated from the rhizome of the plant Curcuma longa, has emerged as a promising anticancer therapeutic agent. However, the mechanism by which curcumin inhibits cancer cell functions such as cell growth, survival, and cell motility is largely unknown. We explored whether curcumin affects the function of integrin alpha(6)beta(4), a laminin adhesion receptor with an established role in invasion and migration of cancer cells. Here we show that curcumin significantly reduced alpha(6)beta(4)-dependent breast cancer cell motility and invasion in a concentration-dependent manner without affecting apoptosis in MDA-MB-435/beta4 (beta(4)-integrin transfectants) and MDA-MB-231 breast cancer cell lines. Further, curcumin selectively reduced the basal phosphorylation of beta(4) integrin (Y1494), which has been reported to be essential in mediating alpha(6)beta(4)-dependent phosphatidylinositol 3-kinase activation and cell motility. Consistent with this finding, curcumin also blocked alpha(6)beta(4)-dependent Akt activation and expression of the cell motility-promoting factor ENPP2 in MDA-MB-435/beta4 cell line. A multimodality approach using curcumin in combination with other pharmacologic inhibitors of alpha(6)beta(4) signaling pathways showed an additive effect to block breast cancer cell motility and invasion. Taken together, these findings show that curcumin inhibits breast cancer cell motility and invasion by directly inhibiting the function of alpha(6)beta(4) integrin, and suggest that curcumin can serve as an effective therapeutic agent in tumors that overexpress alpha(6)beta(4).

Cancer Prev Res (Phila). 2008 Oct;1(5):385-91. PMID: 19138983


Review: Anti cancer effects of curcumin.

ABSTRACT: Increasing knowledge on the cell cycle deregulations in cancers has promoted the introduction of phytochemicals, which can either modulate signaling pathways leading to cell cycle regulation or directly alter cell cycle regulatory molecules, in cancer therapy. Most human malignancies are driven by chromosomal translocations or other genetic alterations that directly affect the function of critical cell cycle proteins such as cyclins as well as tumor suppressors, e.g., p53. In this respect, cell cycle regulation and its modulation by curcumin are gaining widespread attention in recent years. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively non-toxic plant derived polyphenol. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. In the present review we discuss how alterations in the cell cycle control contribute to the malignant transformation and provide an overview of how curcumin targets cell cycle regulatory molecules to assert anti-proliferative and/or apoptotic effects in cancer cells. The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer via an understanding of its mechanism of action at the level of cell cycle regulation. Taken together, this review seeks to summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention.

Cell Div. 2008;3:14. Epub 2008 Oct 3. PMID: 18834508


Curcumin may play a therapeutic role in diseases of the bone associated with osteoclastogenesis and bone lysis.

PURPOSE: Curcumin is a natural polyphenolic derogate extracted from spice turmeric, exhibiting anti-inflammatory and chemopreventive activities. It was described to interact with the signalosome-associated kinases and the proteasome-ubiquitin system, which both are involved in the osteoclastogenesis. Thus, we hypothesized that curcumin could diminish osteoclast differentiation and function.METHODS: For the experiments considering osteoclast differentiation and resorptional activities, preosteoclasts were cultured for 4 weeks and treated with curcumin at subapoptotic dosages. Derived mature osteoclasts were identified as large, multinucleated cells with expression of tartrate-resistant acid phosphatase activity. Formation of resorption lacunae, a hallmark of osteoclast activity, was quantified using dentine pits and light microscopy. The signaling pathways were examined by ELISA-based methods and by immunoblotting.RESULTS: Both 1 and 10 microM curcumin abrogated osteoclast differentiation (by 56 and 81%) and function (by 56 and 99%) (P

J Cancer Res Clin Oncol. 2009 Feb;135(2):173-9. Epub 2008 Sep 3. PMID: 18766375


Curcumin decreases specificity protein expression in bladder cancer cells, indicating it may have anti-cancer properties.

Curcumin is the active component of tumeric, and this polyphenolic compound has been extensively investigated as an anticancer drug that modulates multiple pathways and genes. In this study, 10 to 25 micromol/L curcumin inhibited 253JB-V and KU7 bladder cancer cell growth, and this was accompanied by induction of apoptosis and decreased expression of the proapoptotic protein survivin and the angiogenic proteins vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1). Because expression of survivin, VEGF, and VEGFR1 are dependent on specificity protein (Sp) transcription factors, we also investigated the effects of curcumin on Sp protein expression as an underlying mechanism for the apoptotic and antiangiogenic activity of this compound. The results show that curcumin induced proteasome-dependent down-regulation of Sp1, Sp3, and Sp4 in 253JB-V and KU7 cells. Moreover, using RNA interference with small inhibitory RNAs for Sp1, Sp3, and Sp4, we observed that curcumin-dependent inhibition of nuclear factor kappaB (NF-kappaB)-dependent genes, such as bcl-2, survivin, and cyclin D1, was also due, in part, to loss of Sp proteins. Curcumin also decreased bladder tumor growth in athymic nude mice bearing KU7 cells as xenografts and this was accompanied by decreased Sp1, Sp3, and Sp4 protein levels in tumors. These results show for the first time that one of the underlying mechanisms of action of curcumin as a cancer chemotherapeutic agent is due, in part, to decreased expression of Sp transcription factors in bladder cancer cells.

Cancer Res. 2008 Jul 1;68(13):5345-54. PMID: 18593936


Curcumin prevents progestin-induced breast cancer cell promotion.

OBJECTIVE: Recent clinical trials show that women who receive combined estrogen and progestin hormone therapy (HT) have a higher risk of breast cancer than women who receive estrogen alone or placebo. We have shown that progestins stimulate expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in human breast cancer cells that express the progesterone receptors and mutant p53 protein. Because increased levels of VEGF promote tumor progression, compounds that prevent progestin-induced expression of VEGF could be clinically useful. The objective of this study was to examine whether the polyphenol compound curcumin has the capacity to block progestin-induced secretion of VEGF from T47-D human breast cancer cells.DESIGN: The estrogen and progesterone receptor containing T47-D human breast cancer cells was exposed to 10 nM progesterone or synthetic progestins and varying concentrations of curcumin to determine whether curcumin blocks progestin-dependent production of VEGF from tumor cells.RESULTS: Curcumin (0.001-10 microM for 18 h) reduced medroxyprogesterone acetate (MPA)-induced secretion of VEGF from T47-D cells in a dose-dependent manner. Secretion of VEGF from cells treated with progesterone or progestins other than MPA was unaffected by curcumin.CONCLUSIONS: MPA is the most widely used progestin in HT. Curcumin may therefore provide a clinically useful tool for the suppression of MPA-induced elaboration of VEGF by tumor cells. We propose therefore that clinical trials to assess the beneficial effects of curcumin in postmenopausal women are warranted.

Menopause. 2008 May-Jun;15(3):570-4. PMID: 18467956


Curcumin is a radiosensitizer of human cervical tumor cells.

Cervical cancer is the second most common malignancy among women worldwide and is highly radioresistant, often resulting in local treatment failure. For locally advanced disease, radiation is combined with low-dose chemotherapy; however, this modality often leads to severe toxicity. Curcumin, a polyphenol extracted from rhizomes of the plant Curcuma longa, is a widely studied chemopreventive agent that was shown to have a low toxicity profile in three human clinical trials. Here, we show that pretreatment of two cervical carcinoma cell lines, HeLa and SiHa, with curcumin before ionizing radiation (IR) resulted in significant dose-dependent radiosensitization of these cells. It is noteworthy that curcumin failed to radiosensitize normal human diploid fibroblasts. Although in tumor cells, curcumin did not significantly affect IR-induced activation of AKT and nuclear factor-kappaB, we found that it caused a significant increase in the production of reactive oxygen species, which further led to sustained extracellular signal-regulated kinase (ERK) 1/2 activation. The antioxidant compound N-acetylcysteine blocked the curcumin-induced increased reactive oxygen species (ROS), sustained activation of ERK1/2, and decreased survival after IR in HeLa cells, implicating a ROS-dependent mechanism for curcumin radiosensitivity. Moreover, PD98059 (2'-amino-3'-methoxyflavone)-, PD184352- [2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide], and U0126 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynylthio)butadiene]-specific inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) blocked curcumin-mediated radiosensitization, demonstrating that the sustained ERK1/2 activation resulting from ROS generation leads to curcumin-mediated radiosensitization. Together, these results suggest a novel mechanism for curcumin-mediated radiosensitization involving increased ROS and ERK1/2 activation and suggest that curcumin application (either systemically or topically) may be an effective radiation modifying modality in the treatment of cervical cancer.

Mol Pharmacol. 2008 May;73(5):1491-501. Epub 2008 Feb 5. PMID: 18252805


Curcumin exhibits anti-breast cancer properties.

An important characteristic of tumors is that they at some point in their development overcome the surveillance of the immune system. Tumors secrete exosomes, multivesicular bodies containing a distinct set of proteins that can fuse with cells of the circulating immune system. Purified exosomes from TS/A breast cancer cells, but not non-exosomal fractions, inhibit (at concentrations of nanograms per ml protein) IL-2-induced natural killer (NK) cell cytotoxicity. The dietary polyphenol, curcumin (diferuloylmethane), partially reverses tumor exosome-mediated inhibition of natural killer cell activation, which is mediated through the impairment of the ubiquitin-proteasome system. Exposure of mouse breast tumor cells to curcumin causes a dose-dependent increase in ubiquitinated exosomal proteins compared to those in untreated TS/A breast tumor cells. Furthermore, exosomes isolated from tumor cells pretreated with curcumin have a much attenuated inhibition of IL-2 stimulated NK cell activation. Jak3-mediated activation of Stat5 is required for tumor cytotoxicity of IL-2 stimulated NK cells. TS/A tumor exosomes strongly inhibit activation of Stat5, whereas the tumor exosomes isolated from curcumin-pretreated tumor cells have a lowered potency for inhibition of IL-2 stimulated NK cell cytotoxicity. These data suggest that partial reversal of tumor exosome-mediated inhibition of NK cell tumor cytotoxicity may account for the anti-cancer properties of curcumin.

Biochim Biophys Acta. 2007 Jul;1773(7):1116-23. Epub 2007 May 1. PMID: 17555831


A variety of natural substances may function as novel anticancer agents, proteasome inhibitors and chemosensitizers.

A major challenge in cancer therapy is tumor drug resistance. To overcome it, it is essential to understand the mechanisms and identify the molecules involved, so that they can be specifically targeted in combination therapies. The proteasome is such a validated target: it plays a key role in cancer cell proliferation, inhibition of chemotherapy-induced apoptosis and drug resistance development. Bortezomib (Velcade, PS-341) was the first proteasome inhibitor to receive regulatory approval from the US Food and Drug Administration for the treatment of multiple myeloma. Clinical combination trials have demonstrated a chemo-sensitizing effect of bortezomib on conventional agents in hematological malignancies and some solid tumors such as androgen-independent prostate and ovarian cancer. Although generally well-tolerated, bortezomib still generates toxicity which underscores the need for less toxic proteasome inhibitors. Several naturally occurring products, such as green tea polyphenols and the antibiotic lactacystin, have been shown to be potent proteasome inhibitors. Significantly, green tea polyphenols, as well as several flavonoids such as genistein, curcumin and resveratrol, have also been shown to have chemo-sensitizing properties in prostate, breast, hepatic, and lung tumors. Further studies on natural proteasome inhibitors as chemo-sensitizers could lead to identification of more potent and less toxic compounds that could be used in combination therapies for drug-resistant tumors.

Drug Resist Updat. 2006 Dec;9(6):263-73. Epub 2007 Jan 2. PMID: 17197231


Ellagic acid and curcumin may inhibit cancer through preventing the over-expression of glutathione S-transferases.

Glutathione S-transferases (GSTs) are multifunctional detoxification proteins that protect the cell from electrophilic compounds. Overexpression of GSTs in cancer results in resistance to chemotherapeutic agents and inhibition of the over expressed GST has been suggested as an approach to combat GST-induced resistance. The inhibition of human recombinant GSTs by natural plant products was investigated in this study. Using 1-chloro-2,4 dinitrobenzene (CDNB) as a substrate, ellagic acid and curcumin were shown to inhibit GSTs A1-1, A2-2, M1-1, M2-2 and P1-1 with IC(50) values ranging from 0.04 to 5 microM whilst genistein, kaempferol and quercetin inhibited GSTs M1-1 and M2-2 only. The predominant mode of inhibition with respect to the G and H-sites were mixed inhibition and uncompetitive to a lesser extent. The K(i) (K(i)(')) values for ellagic acid and curcumin with respect to GSH and CDNB were in the range 0.04-6 microM showing the inhibitory potency of these polyphenolic compounds. Ellagic acid and curcumin also showed time- and concentration-dependent inactivation of GSTs M1-1, M2-2 and P1-1 with curcumin being a more potent inactivator than ellagic acid. These results facilitate the understanding of the interaction of human GSTs with plant polyphenolic compounds with regards to their role as chemomodulators in cases of GST-overexpression in malignancies.

Food Chem Toxicol. 2007 Feb;45(2):286-95. Epub 2006 Aug 30. PMID: 17046132


Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells.

Curcumin (diferuloylmethane), a polyphenol natural product of the plant Curcuma longa, is undergoing early clinical trials as a novel anticancer agent. However, the anticancer mechanism of curcumin remains to be elucidated. Here we show that curcumin inhibited growth of rhabdomyosarcoma cells (Rh1 and Rh30) (IC50 = 2-5 microM) and arrested cells in G1 phase of the cell cycle. Curcumin also induced apoptosis and inhibited the basal or type I insulin-like growth factor-induced motility of the cells. At physiological concentrations (2.5 microM), curcumin rapidly inhibited phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream effector molecules, p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), in a panel of cell lines (Rh1, Rh30, DU145, MCF-7 and Hela). Curcumin also inhibited phosphorylation of Akt in the cells, but only at high concentrations (>40 microM). The data suggest that curcumin may execute its anticancer activity primarily by blocking mTOR-mediated signaling pathways in the tumor cells.

Int J Cancer. 2006 Aug 15;119(4):757-64. PMID: 16550606


Curcumin displays therapeutic activity in experimental studies of acute and chronic diseases characterized by an exaggerated inflammatory reaction.

BACKGROUND: The world suffers a tsunami of chronic diseases, and a typhoon of acute illnesses, many of which are associated with the inappropriate or exaggerated activation of genes involved in inflammation. Finding therapeutic agents which can modulate the inflammatory reaction is the highest priority in medical research today. Drugs developed by the pharmaceutical industry have thus far been associated with toxicity and side effects, which is why natural substances are of increasing interest.METHODS: A literature search (PubMed) showed almost 1500 papers dealing with curcumin, most from recent years. All available abstracts were read. Approximately 300 full papers were reviewed.RESULTS: Curcumin, a component of turmeric, has been shown to be non-toxic, to have antioxidant activity, and to inhibit such mediators of inflammation as NFkappaB, cyclooxygenase-2 (COX-2), lipooxygenase (LOX), and inducible nitric oxide synthase (iNOS). Significant preventive and/or curative effects have been observed in experimental animal models of a number of diseases, including arteriosclerosis, cancer, diabetes, respiratory, hepatic, pancreatic, intestinal and gastric diseases, neurodegenerative and eye diseases.CONCLUSIONS: Turmeric, an approved food additive, or its component curcumin, has shown surprisingly beneficial effects in experimental studies of acute and chronic diseases characterized by an exaggerated inflammatory reaction. There is ample evidence to support its clinical use, both as a prevention and a treatment. Several natural substances have greater antioxidant effects than conventional vitamins, including various polyphenols, flavonoids and curcumenoids. Natural substances are worth further exploration both experimentally and clinically.

Horm Behav. 1978 Feb;10(1):54-60. PMID: 16387899


A number of plant polyphenols have chemosensitizing and radiosensitizing activity.

The treatment of cancer with chemotherapeutic agents and radiation has two major problems: time-dependent development of tumor resistance to therapy (chemoresistance and radioresistance) and nonspecific toxicity toward normal cells. Many plant-derived polyphenols have been studied intently for their potential chemopreventive properties and are pharmacologically safe. These compounds include genistein, curcumin, resveratrol, silymarin, caffeic acid phenethyl ester, flavopiridol, emodin, green tea polyphenols, piperine, oleandrin, ursolic acid, and betulinic acid. Recent research has suggested that these plant polyphenols might be used to sensitize tumor cells to chemotherapeutic agents and radiation therapy by inhibiting pathways that lead to treatment resistance. These agents have also been found to be protective from therapy-associated toxicities. How these polyphenols protect normal cells and sensitize tumor cells to treatment is discussed in this review.

Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1630-47. PMID: 16356126


Curcumin suppresses protein kinase C and nuclear oncogene expression associated with cancer progression.

Curcumin (diferuloylmethane) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animal models. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase; and an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF(Epidermal growth factor)-receptor tyrosine kinase and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF(nucleor factor)kappaB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, while the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the major metabolites of curcumin in mice, rats and humans.

Arch Pharm Res. 2004 Jul;27(7):683-92. PMID: 15356994


Six dietary constituents inhibit nicotine-DNA adduct formation.

Nicotine [3-(1-methyl-2-pyrrolidinyl)-pyridine] is a major alkaloid in tobacco products and has proven to be a potential genotoxic compound. Many natural dietary products can suppress the DNA adduction, and hence act as inhibitors of cancer. In this study, we investigated the inhibitory effects of curcumin, garlic squeeze, grapeseed extract, tea polyphenols, vitamin C, and vitamin E on nicotine-DNA adduction in vivo using an ultrasensitive method of accelerator mass spectrometry (AMS). The results demonstrated that all the dietary constituents induced marked dose-dependent decrease in nicotine-DNA adducts as compared with the control. The reduction rate reached about 50% for all agents, except garlic squeeze (40%), even at its highest dose level. Amongst the six agents, grapeseed extract exhibited the strongest inhibition to the DNA adduct formation. Therefore, we may arrive at a point that these dietary constituents are beneficial to prevent the harmful adduct formation, and thus to block the potential carcinogenesis induced by nicotine.

Food Chem Toxicol. 2003 Jul;41(7):1045-50. PMID: 12804663


Curcumin may prevent ferric nitrilotriacetate (Fe-NTA) induced toxicity and cancer.

A number of investigations have implicated the involvement of free radicals in various pathogenic process including initiation/promotion stages of carcinogenesis and antioxidants have been considered to be a protective agent for this reason. An iron chelate, ferric nitrilotriacetate (Fe-NTA), is a potent nephrotoxic agent and induces acute and subacute renal proximal tubular necrosis by catalyzing the decomposition of hydrogen peroxide-derived production of hydroxyl radicals, which are known to cause lipid peroxidation and DNA damage. The latter is associated with a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation and DNA damage are the principal manifestation of Fe-NTA-induced toxicity, which could be mitigated by antioxidants. In this study, we therefore investigated the effect of curcumin, a polyphenolic compound from Curcuma longa for a possible protection against lipid peroxidation and DNA damage induced by Fe-NTA and hydrogen peroxide in vitro. Incubation of renal microsomal membrane/and or calf thymus DNA with hydrogen peroxide (40 mM) in the presence of Fe-NTA (0.1 mM) induces renal microsomal lipid peroxidation and DNA damage to about 2.2-and 5.6-fold, respectively, as compared to saline treated control (P

J Cutan Pathol. 2009 Oct;36(10):1053-62. Epub 2009 Jan 27. PMID: 12616605


Curcumin inhibits Helicobacter pylori.

BACKGROUND: Curcumin, a polyphenolic chemical constituent derived from turmeric (Curcuma longa), has been shown to prevent gastric and colon cancers in rodents. Many mechanisms have been proposed for the chemopreventative effects, although the effect of curcumin on the growth of Helicobacter pylori has not been reported. H. pylori is a Group 1 carcinogen and is associated with the development of gastric and colon cancer.MATERIALS AND METHODS: A methanol extract of the dried powdered turmeric rhizome and curcumin were tested against 19 strains of H. pylori, including 5 cagA+ strains.RESULTS: Both the methanol extract and curcumin inhibited the growth of all strains of H. pylori in vitro with a minimum inhibitory concentration range of 6.25-50 micrograms/ml.CONCLUSION: These data demonstrate that curcumin inhibits the growth of H. pylori cagA+ strains in vitro, and this may be one of the mechanisms by which curcumin exerts its chemopreventative effects.

Anticancer Res. 2002 Nov-Dec;22(6C):4179-81. PMID: 12553052


Curcumin inhibits growth and sensitizes ovarian cancer cells to cisplatin-mediated killing.

The polyphenolic compounds curcumin and quercetin increased sensitivity of ovarian cancer cells (CAOV3 and SKOV3) to cisplatin. The effect was obtained when the compounds were added simultaneously with cisplatin, as well as when they were added 24 h before. High serum levels of certain cytokines, for example interleukin-6 (IL-6), have been associated with poor prognosis and cisplatin resistance in various forms of cancer. Furthermore, it has been hypothesized that cytokines may increase proliferation, metastasis, and stimulate production of detoxification enzymes and multi-drug resistant proteins. Curcumin inhibits the production of many cytokines. The two ovarian cell lines differ significantly in IL-6 production, and correspondingly the high producer, CAOV3, was less susceptible to cisplatin. Curcumin inhibited the production of IL-6 in this cell suggesting that one of the mechanisms for synergy between cisplatin and curcumin was by reducing the autologous production of IL-6. However, the synergy was also observed in the low IL-6 producer, SKOV3, indicating that the action was most probably a result of multiple targeting. In sum, this study suggests that the compounds, curcumin and quercetin, potentially may be useful for enhancing drug sensitivity in certain cancer.

Carcinogenesis. 1982;3(11):1331-8. PMID: 12447990


Curcumin, EGCG and resveratrol inhibit inflammation.

A wide array of phenolic substances, particularly those present in edible and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Cyclooxygenase-2 (COX-2) inducible and nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. Improper up-regulation of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage. Examples are curcumin, a yellow pigment of turmeric (Curcuma longa L., Zingiberaceae), the green tea polyphenol epigallocatechin gallate (EGCG), and resveratrol from grapes (Vitis vinifera, Vitaceae) that strongly suppress tumor promotion. Recent studies have demonstrated that eukaryotic transcription factor nuclear factor-kappa B (NF-kappa B) is involved in regulation of COX-2 and iNOS expression. Several chemopreventive phytochemicals have been shown to inhibit COX-2 and iNOS expression by blocking improper NF-kappa B activation. Multiple lines of compelling evidence indicate that extracellular-regulated protein kinase and p38 mitogen-activated protein kinase are key elements of the intracellular signaling cascades responsible for NF-kappa B activation in response to a wide array of external stimuli. Curcumin, EGCG and resveratrol have been shown to suppress activation of NF-kappa B. One of the plausible mechanisms underlying inhibition of NF-kappa B activation by aforementioned phytochemicals involves repression of degradation of the inhibitory unit I kappa B alpha, which hampers subsequent nuclear translocation of the functionally active subunit of NF-kappa B.

Mutat Res. 2001 Sep 1;480-481:243-68. PMID: 11506818


Curcumin inhibits lipoxygenase, indicating it possesses anti-inflammatory and anti-cancer properties.

Many lipoxygenase inhibitors including curcumin are currently being studied for their anti-carcinogenic properties. Curcumin is a naturally occurring polyphenolic phytochemical isolated from the powdered rhizome of the plant Curcuma longa that possesses anti-inflammatory properties and inhibits cancer formation in mice. Recently it was shown that the soybean lipoxygenase L1 catalyzed the oxygenation of curcumin and that curcumin can act as a lipoxygenase substrate. In the current study, we investigated the fate of curcumin when used as a soybean lipoxygenase L3 substrate. By use of X-ray diffraction and mass spectrometry, we found an unoccupied electron mass that appears to be an unusual degradation product of curcumin (4-hydroxyperoxy-2-methoxyphenol) located near the soybean L3 catalytic site. Understanding how curcumin inhibits lipoxygenase may help in the development of novel anti-cancer drugs used for treatment where lipoxygenases are involved.

Int J Mol Med. 2000 Nov;6(5):521-6. PMID: 11029517


Resveratrol is an inducer of multiple pathways of cancer cell death.

Cancers are the largest cause of mortality and morbidity in industrialized countries. In the field of the medicinal chemistry of natural products, numerous studies have reported interesting properties of trans-resveratrol as a chemopreventing agent against cancers, inflammation, and viral infection. Tumor growth inhibition has been linked to the ability of resveratrol to arrest cell cycle progression and to trigger cell death. This review focuses on the pathways that mediate resveratrol-induced cell death. Resveratrol impacts on the mitochondrial functions (respiratory chain, oncoproteins, gene expression, etc), in which p53 protein can be involved and its acetylated or phosphorylated forms. This polyphenol also affects death receptor distribution in ceramide-enriched membrane platforms which serve to trap and cluster receptor molecules, and facilitates the formation of a death-inducing signaling complex in the cell. To induce apoptosis, resveratrol also activates the ceramide / sphingomyelin pathway, which promotes ceramide generation and the downstream activation of kinase cascades. Resveratrol can activate alternative pathways to cell death such as those leading to autophagy, senescence or mitotic catastrophe. Furthermore, numerous attempts have been made using resveratrol analogs to improve the molecule's ability to block cell proliferation and induce cell death. Moreover, structural modification of natural phenolics is expected to produce analogs that may be useful tools to study the structure-activity relationships. Lastly, in various cancer types, resveratrol behaves as a chemosensitizer that lowers the threshold of cell death induction by classical anticancer agents and counteracts tumor cell chemoresistance.

Curr Med Chem. 2011 Feb 3. Epub 2011 Feb 3. PMID: 21291372


Resveratrol exhibits anti-proliferative effects against breast cancer cells.

Resveratrol is a grape polyphenol with cancer preventative activities in tissue culture and animal model studies. Potential of resveratrol as a broad-based chemopreventive agent have been questioned by its limited bioavailability. The bioefficacy of resveratrol was compared with its derivatives, triacetyl-resveratrol (trans-3,5,4'-triacetylstilbene) and trimethoxy-resveratrol (trans-3,5,4'-trimethoxystilbene) in both estrogen receptor-α (ERα)-positive MCF-7 and ERα-negative MDA-MB-231 breast cancer cells. Binding to integrin αvβ3 and control of cell proliferation and p53 were chosen as targets for comparative analysis using an in silico and biochemical approach.Resveratrol and triacetyl-resveratrol interacted avidly and specifically with integrin αvβ3 through binding at the site targeted by the high affinity cyclic Arg-Gly-Asp (RGD) peptide. In contrast, binding of trimethoxy-resveratrol to this site was substantially less robust. Moreover, the different stilbenes also elicited diverse cellular and signaling responses in MCF-7 and MDA-MB-231 cells, as evidenced by analysis of colony formation, cell proliferation, cell cycle phase transition, the extent of phosphorylation of p53 at Ser15 and p53-inducible proteins, p21 and p53R2, respectively. Further, stilbene-elicited signaling cascade leading to p53 activation was examined in MCF-7 cells and results showed that resveratrol and triacetyl-resveratrol induced both ERK and p38 phosphorylation, whereas only marginal changes in state of phosphorylation in these two kinases were observed in trimethoxy-resveratrol-treated cells. Taken together, these results support that resveratrol and triacetyl-resveratrol regulate proliferation and gene expression in breast cancer cells by utilizing largely similar signaling molecules and pathways and cellular events, which appear quite distinct from those targeted by trimethoxy-resveratrol.

Int J Cancer. 2011 Jan 10. Epub 2011 Jan 10. PMID: 21225623


Resveratrol exhibits anti-inflammatory properties.

Resveratrol (trans-3,4',5-trihydroxystilbene) is one of nonflavonoid polyphenolic phytoalexins found in various plant species, a number of which are components of human diet including grapes and red wines. Resveratrol has exerted several beneficial effects with anti-inflammation, cardioprotection and cancer chemoprevention. However, its mechanisms of action are not completely understood. In this study, we investigated effects of resveratrol on inflammatory gene expression in interferon (IFN)-γ alone-stimulated macrophages and proposed a molecular basis underlying the action. Resveratrol inhibited IFN-γ-induced production of nitric oxide (NO), IFN-γ-inducible protein-10 (IP-10), or the monokine induced by IFN-γ (MIG) in RAW 264.7 macrophages and also that of NO in primary macrophagesderived from bone marrows of C3H/HeJ (toll-like receptor-4(-/-)) mice. Moreover, resveratrol diminished IFN-γ-induced protein levels of inducible NO synthase (iNOS), attenuated mRNA levels of iNOS, IP-10 or MIG as well as inhibited IFN-γ-induced promoter activity of iNOS gene, indicating that thephytoalexin could down-regulate inflammatory genes at the transcription level. To understand a mechanism of the action, we tested resveratrol could affect the signal transducers and activation of transcription-1 (STAT-1), a pivotal transcription factor in IFN-γ-induced expression of inflammatory genes. Resveratrol inhibited IFN-γ-induced transcriptional activity of STAT-1 in macrophages and also IFN-γ-induced Tyr(701) or Ser(727) phosphorylation of STAT-1. We then focused on protein kinases upstream STAT-1 phosphorylation. Resveratrol inhibited IFN-γ-induced activation of Janus kinase-2 (JAK-2) and also the extracellular signal-regulated kinase, in which JAK-2 was more sensitive. Taken together, this study proposes a new mechanism of resveratrol, blocking JAK/STAT-1 pathway that controls inflammatory responses in IFN-γ-activated macrophages.

J Nutr Biochem. 2010 Dec 27. Epub 2010 Dec 27. PMID: 21189227


Resveratrol induces growth arrest and programmed cell death in prostate cancer cells.

BACKGROUND: Resveratrol, a naturally occurring phytopolyphenol compound, has attracted extensive interest in recent years because of its diverse pharmacological characteristics. Although resveratrol possesses chemopreventive properties against several cancers, the molecular mechanisms by which it inhibits cell growth and induces apoptosis have not been clearly understood. The present study was carried out to examine whether PI3K/AKT/FOXO pathway mediates the biological effects of resveratrol.METHODOLOGY/PRINCIPAL FINDINGS: Resveratrol inhibited the phosphorylation of PI3K, AKT and mTOR. Resveratrol, PI3K inhibitors (LY294002 and Wortmannin) and AKT inhibitor alone slightly induced apoptosis in LNCaP cells. These inhibitors further enhanced the apoptosis-inducing potential of resveratrol. Overexpression of wild-type PTEN slightly induced apoptosis. Wild type PTEN and PTEN-G129E enhanced resveratrol-induced apoptosis, whereas PTEN-G129R had no effect on proapoptotic effects of resveratrol. Furthermore, apoptosis-inducing potential of resveratrol was enhanced by dominant negative AKT, and inhibited by wild-type AKT and constitutively active AKT. Resveratrol has no effect on the expression of FKHR, FKHRL1 and AFX genes. The inhibition of FOXO phosphorylation by resveratrol resulted in its nuclear translocation, DNA binding and transcriptional activity. The inhibition of PI3K/AKT pathway induced FOXO transcriptional activity resulting in induction of Bim, TRAIL, p27/KIP1, DR4 and DR5, and inhibition of cyclin D1. Similarly, resveratrol-induced FOXO transcriptional activity was further enhanced when activation of PI3K/AKT pathway was blocked. Over-expression of phosphorylation deficient mutants of FOXO proteins (FOXO1-TM, FOXO3A-TM and FOXO4-TM) induced FOXO transcriptional activity, which was further enhanced by resveratrol. Inhibition of FOXO transcription factors by shRNA blocked resveratrol-induced upregulation of Bim, TRAIL, DR4, DR5, p27/KIP1 and apoptosis, and inhibition of cyclin D1 by resveratrol.CONCLUSION/SIGNIFICANCE: These data suggest that FOXO transcription factors mediate anti-proliferative and pro-apoptotic effects of resveratrol, in part due to activation of extrinsic apoptosis pathway.

PLoS One. 2010;5(12):e15288. Epub 2010 Dec 14. PMID: 21179458


Resveratrol may reduce prostate-specific antigen by inhibiting androgen receptor

Androgen receptor (AR) is a ligand-dependent transcription factor and plays a key role in the development of prostate cancer. Resveratrol, a polyphenolic compound, inhibits AR function and reduces the level of prostate-specific antigen (PSA), a notable target gene of AR. Here, we investigated the mechanisms by which resveratrol inhibits AR function. Although the protein levels of AR were decreased by resveratrol treatment for 24h, the decrease could not fully account for the suppression of AR function. The total and the nuclear AR levels were not affected after incubation with 10μM resveratrol for 3h, whereas resveratrol inhibited the binding of AR to the enhancer region of PSA and decreased the acetylation of AR even at this early phase. Inhibition of transcription by resveratrol was weaker in the AR acetylation site mutant than in the wild-type. In later phase (24h) after incubation with resveratrol, the ligand-induced nuclear accumulation of AR was markedly decreased by resveratrol. These data show that resveratrol inhibits DNA binding of AR, presumably by decreasing its level of acetylation and suggest that acetylation of AR is involved in its accumulation in thenucleus.

J Steroid Biochem Mol Biol. 2011 Jan;123(1-2):65-70. Epub 2010 Nov 10. PMID: 21073951


Resveratrol inhibited the proliferation of pancreatic cancer cells by inducing programmed cell death.

To investigate resveratrol, one of the food derived polyphenols that might be partially responsible for the beneficial effect on cancer, the in vitro antitumor activity of resveratrol against pancreatic cancer cell lines (PANC-1, BxPC-3 and AsPC-1) was examined, together with the mechanisms involved. The effects of resveratrol on the growth inhibition, apoptosis and cell cycle were assayed. The activity of caspases and the expression of Bcl-2, Bcl-xL, XIAP and Bax protein were detected. The results showed that resveratrol inhibited the proliferation of pancreatic cancer cells in a dose- and time-dependent manner. Resveratrol inhibited the cell growth of PANC-1, BxPC-3 and AsPC-1 cells with IC(50) values of 78.3± 9.6 μmol/L, 76.1 ± 7.8 μmol/L and 123.1 ± 6.5 μmol/L at 48 h, respectively. Incubation of pancreatic cancer cells with resveratrol resulted in cell apoptosis and cell cycle arrests. Resveratrol induced activation of caspases. Simultaneously, resveratrol regulated the expression of the antiapoptotic proteins Bcl-2, Bcl-xL and XIAP and the proapoptotic protein Bax. PANC-1 and BxPC-3 cells were more chemosensitive to resveratrol than AsPC-1 cells. In conclusion, resveratrol inhibited the proliferation of pancreatic cancer cells by inducing apoptotic cell death. There was different sensitivity to resveratrol in different pancreatic cancer cell lines.

Phytother Res. 2010 Nov;24(11):1637-44. PMID: 21031621


Resveratrol, a red wine polyphenol, suppresses pancreatic cancer.

The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4'-trihydroxy-trans -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied leukotriene A(4) hydrolase (LTA(4)H) as a relevant target in pancreatic cancer. LTA(4)H knockdown limited the formation of leukotriene B(4) (LTB(4)), the enzymatic product of LTA(4)H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA(4)H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA(4)H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB(4) production and expression of the LTB(4) receptor 1 (BLT(1)). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA(4)H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA(4)H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA(4)H activity. Our findings identify LTA(4)H as a functionally important target for mediating the anticancer properties of resveratrol.

Cancer Res. 2010 Dec 1;70(23):9755-64. Epub 2010 Oct 15. PMID: 20952510


Resveratrol may have significant antioxidant effects in erythrocytes, leading to an increase in plasma antioxidant potential.

Resveratrol is one of the most widely studied of all the plant-produced polyphenols and has diverse, beneficial health effects including anti-cancer and cardio-protective effects. Many of the biological actions of this polyphenol have been attributed to its antioxidant properties. Erythrocytes contain a plasma membrane redox system (PMRS), which transfers electrons from intracellular donors (NADH and/or ascorbate (ASC)) to extracellular acceptors. There is evidence that the intracellular ASC donates electrons to extracellular ascorbate free radicals (AFRs) via the PMRS, which encompasses an AFR reductase; such a redox system enables the cells to effectively counteract oxidative processes.We present evidence to show that human erythrocytes take up resveratrol, and once inside the cell, resveratrol can donate electrons to extracellular electron acceptors through the erythrocyte PMRS and AFR reductase. Incubating human erythrocytes with resveratrol (10μM) caused a significant activation of the PMRS (41%) and AFR reductase (30%) over (basal level) the control; the effect of resveratrol was concentration-dependent. The electron donating ability of resveratrol is slightly less than that observed with quercetin. The role of resveratrol in activatingthe erythrocyte PMRS and AFR reductase may assume significance in all disease conditions in which there is a decrease in plasma antioxidant potential.

Pharmacol Rep. 2010;62(4):726-32. PMID: 20885013


Resveratrol possesses unique properties with therapeutic potentials for the treatment of cardiovascular diseases.

Resveratrol (3,4',5-trihydroxystilbene) is a member of natural, plant-derived chemicals known as polyphenols and is attracting increased attention due to its diverse health benefits especially in case of cardiovascular disease, cancer, diabetes and neurological problems. Despite impressive gains in diagnosis and treatment, cardiovascular disease (CVD) remains a serious clinical problem and threat to public health. Resveratrol possesses potent antioxidant properties and has been shown to decrease low-density lipoprotein-cholesterol oxidation and platelet aggregation. This compound also possesses a range of additional cardioprotective and vasoprotective properties including antiatherosclerotic and vasorelaxation action. Resveratrol also has the capacity to interact with multiple molecular targets, which involve diverse intracellular pathways. Most well-known is the ability of resveratrol to activate sirtuins, a class of NAD(+)-dependent deacetylase that affect multiple transcription factors and other protein targets. Recently, resveratrol was found to induce autophagy and regenerate myocardial ischemic tissue treated with stem cells. Overall observation indicates that resveratrol has a high therapeutic potentials for the treatment of cardiovascular diseases.

Mol Aspects Med. 2010 Dec;31(6):503-12. Epub 2010 Sep 15. PMID: 20837050


Resveratrol has anti-inflammatory and neuroprotective properties in a neurological tissue culture.

BACKGROUND: Inflammatory responses in the CNS mediated by activated glial cells play an important role in host-defense but are also involved in the development of neurodegenerative diseases. Resveratrol is a natural polyphenolic compound that has cardioprotective, anticancer and anti-inflammatory properties. We investigated the capacity of resveratrol to protect microglia and astrocyte from inflammatory insults and explored mechanisms underlying different inhibitory effects of resveratrol on microglia and astrocytes.METHODS: A murine microglia cell line (N9), primary microglia, or astrocytes were stimulated by LPS with or without different concentrations of resveratrol. The expression and release of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6, MCP-1) and iNOS/NO by the cells were measured by PCR/real-time PCR and ELISA, respectively. The phosphorylation of the MAP kinase superfamily was analyzed by western blotting, and activation of NF-kappaB and AP-1 was measured by luciferase reporter assay and/or electrophoretic mobility shift assay.RESULTS: We found that LPS stimulated the expression of TNF-alpha, IL-1beta, IL-6, MCP-1 and iNOS in murine microglia and astrocytes in which MAP kinases, NF-kappaB and AP-1 were differentially involved. Resveratrol inhibited LPS-induced expression and release of TNF-alpha, IL-6, MCP-1, and iNOS/NO in both cell types with more potency in microglia, and inhibited LPS-induced expression of IL-1beta in microglia but not astrocytes. Resveratrol had no effect on LPS-stimulated phosphorylation of ERK1/2 and p38 in microglia and astrocytes, but slightly inhibited LPS-stimulated phosphorylation of JNK in astrocytes. Resveratrol inhibited LPS-induced NF-kappaB activation in both cell types, but inhibited AP-1 activation only in microglia.CONCLUSION: These results suggest that murine microglia and astrocytes produce proinflammatory cytokines and NO in response to LPS in a similar pattern with some differences in signaling molecules involved, and further suggest that resveratrol exerts anti-inflammatory effects in microglia and astrocytes by inhibiting different proinflammatory cytokines and key signaling molecules.

J Neuroinflammation. 2010;7:46. Epub 2010 Aug 17. PMID: 20712904


Resveratrol attenuates radiation damage.

Resveratrol, a member of a class of polyphenolic compounds known as flavonols, has been extensively studied for its anticancer, antiviral, anti-inflammatory, and neuroprotective roles. Caenorhabidits elegans is a well-established animal for investigating responses to radiation. We found that resveratrol may provide protection against hazardous radiation. Pre-treatment with resveratrol extended both the maximum and mean life span of irradiated C. elegans. Resveratrol acted as a strong radical scavenger and regulated superoxide dismutase (SOD) expression. In addition, resveratrol was shown to be capable of alleviating gamma-ray radiation exposure-induced reduction in mitochondrial SOD expression. Ultimately, a correlation may exist between dietary intake of trace amounts of resveratrol and anti-aging effects. A specific response mechanism may be activated after the administration of resveratrol in irradiated animals. Our results suggest the protective effect of resveratrol is due to its strong ability to protect from oxidative stress and protective effects in mitochondria. Therefore, resveratrol is potentially an effective protecting agent against irradiative damage.

Chemosphere. 2003 Dec;53(8):883-8. PMID: 20679743


Resveratrol may have therapeutic value in liver disease.

Liver diseases incorporate several maladies, which can range from benign histological changes to serious life-threatening conditions. These may include inborn metabolic disease, primary and metastatic cancers, alcoholic cirrhosis, viral hepatitis and drug-induced hepatotoxicity. Liver disease remains a major cause of morbidity and mortality with significant economic and social costs. Several novel approaches are currently being studied which may provide a better therapeutic outcome. The use of naturally occurring phytochemicals, some of them obtained from dietary sources, in the amelioration of illness have recently gained considerable popularity. These agents, having anti-oxidant and anti-inflammatory properties, provide a safe and effective means of ameliorating chronic disease. Resveratrol, a grape polyphenol, has shown considerable promise as a therapeutic agent in the treatment of the aforementioned liver ailments. Several studies have highlighted the hepatoprotective properties of resveratrol. Resveratrol has been shown to prevent hepatic damage because of free radicals and inflammatory cytokines, induce anti-oxidant enzymes and elevate glutathione content. Resveratrol has also been shown to modulate varied signal transduction pathways implicated in liver diseases. This review critically examines the current preclinical in vitro and in vivo studies on the preventive and therapeutic effects of resveratrol in liver diseases. The review highlights the pharmacological mechanisms involved in mediating the aforementioned effects. Toxicity, pharmacokinetics and clinical bioavailability of resveratrol are also reviewed in this article. The challenges involved, future directions and novel approaches such as site-specific drug delivery in the use of resveratrol for the prevention and treatment of liver disease are also discussed.

Liver Int. 2010 Sep;30(8):1103-14. Epub 2010 Jun 14. PMID: 20557453


Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity.

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by a progressive loss of dopamine (DA) neurons in the substantia nigra. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for PD. Resveratrol, a nonflavonoid polyphenol naturally found in red wine and grapes, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. Although recent studies have shown that resveratrol provided neuroprotective effects against ischemia, seizure, and neurodegenerative disorders, the mechanisms underlying its beneficial effects on dopaminergic neurodegeneration are poorly defined. In this study, rat primary midbrain neuron-glia cultures were used to elucidate the molecular mechanisms underlying resveratrol-mediated neuroprotection. The results clearly demonstrated that resveratrol protected DA neurons against lipopolysaccharide (LPS)-induced neurotoxicity in concentration- and time-dependent manners through the inhibition of microglial activation and the subsequent reduction of proinflammatory factor release. Mechanistically, resveratrol-mediated neuroprotection was attributed to the inhibition of NADPH oxidase. This conclusion is supported by the following observations. First, resveratrol reduced NADPH oxidase-mediated generation of reactive oxygen species. Second, LPS-induced translocation of NADPH oxidase cytosolic subunit p47 to the cell membrane was significantly attenuated by resveratrol. Third and most importantly, resveratrol failed to exhibit neuroprotection in cultures from NADPH oxidase-deficient mice. Furthermore, this neuroprotection was also related to an attenuation of the activation of mitogen-activated protein kinases and nuclear factor-kappaB signaling pathways in microglia. These findings suggest that resveratrol exerts neuroprotection against LPS-induced dopaminergic neurodegeneration, and NADPH oxidase may be a major player in resveratrol-mediated neuroprotection.

Mol Pharmacol. 2010 Sep 1;78(3):466-77. Epub 2010 Jun 16. PMID: 20554604


Resveratrol has anti-atherogenic properties.

Resveratrol (RS), a polyphenol compound found in grapes and grape products, including wine, peanuts and berries, exists in cis- and trans-isomeric forms. RS is believed to decrease circulating low-density lipoprotein cholesterol levels and reduce cardiovascular disease (CVD) risk. However, it is possible that RS has other mechanisms to reduce the risk of CVD without altering lipid levels. The objective of this review is to critically examine results from recent research concerning potential effects of RS on CVD. RS exerts several health benefits including anti-atherogenic, anti-inflammatory and anti-cancer effects. RS may also prevent lipid oxidation, platelet aggregation, arterial vasodilation and modulates the levels of lipids and lipoproteins. As a potent, anti-oxidant RS reduces oxidative stress and regenerates alpha-tocopherol, which further strengthens the anti-oxidant defense mechanism. RS has been considered safe as no significant toxic effects have been identified, even when consumed at higher concentrations. This evidence identified RS as an effective anti-atherogenic agent, which could be used in the prevention and treatment of CVD.

Eur J Clin Nutr. 2010 Jul;64(7):660-8. Epub 2010 May 19. PMID: 20485301


Wine polyphenolic extracts have a cytotoxic effect against human cancer cell lines.

Red and white wine polyphenols have been reported to provide substantial health benefits. In this study, the cytotoxic activity of red and white wine polyphenolic extracts and of resveratrol was evaluated against different cancer cell lines--human cervix adenocarcinoma HeLa, human breast adenocarcinoma MDA-MB-361, and human breast carcinoma MDA-MB-453--and normal human peripheral blood mononuclear cells (PBMCs). Qualitative and quantitative compositions of wine polyphenolic extracts obtained by fractional vacuum distillation of corresponding wines were determined using spectrophotometric methods and high-performance liquid chromatography with diode array detection and liquid chromatography with electrospray ionization-time of flight mass spectrometry analysis. It was demonstrated that wine polyphenolic extracts and resveratrol exerted higher cytotoxic activity against HeLa and MDA-MB-453 cells in comparison to MDA-MB-361 cells and unstimulated and stimulated PBMCs. Furthermore, white wine polyphenolic extract exhibited a significantly higher antiproliferative action on cancer cell lines than red wine extract. The presence of condensed or fragmented nuclei in HeLa cells, pretreated with extract of white wine and stained with a mixture of acridine orange and ethidium bromide, pointed to the morphological signs of apoptosis. In addition, HeLa cells in late stages of apoptosis or secondary necrosis were also observed. Results from our study suggest that polyphenolic extracts from red and white wine may have anticarcinogenic potential.

J Med Food. 2010 Aug;13(4):851-62. PMID: 20482276


Resveratrol has anti-inflammatory properties in the brain.

Neuroinflammation is an important contributor to pathogenesis of neurological disorders, with microglial activation as a hallmark of neuroinflammation. Microglia serve the role of immune surveillance under normal conditions, but after brain damage or exposure to inflammation, microglia are activated and secrete pro-inflammatory and neurotoxic mediators. Sustained production of these factors contributes to neuronal damage. Therefore, inhibition of microglia-mediated neuroinflammation may become a promising therapeutic target for neurological disorders. Resveratrol, a non-flavonoid polyphenol rich in red wine and grapes, has beneficial health effects from its antioxidant, anticancer and anti-inflammatory properties. Recently, resveratrol has been shown to protect against various neurological disorders in experimental models, including brain ischemia, seizures, and neurodegenerative disease models. This minireview summarized the anti-inflammatory activities of resveratrol in the brain from both in vivo and in vitro studies, and highlighted the inhibition of activated microglia as a potential mechanism of neuroprotection. The release of various pro-inflammatory factors, the production of reactive oxygen species, and the activation of signal pathways leading to neuroinflammation were discussed in relation to microglial activation. Taken together, microglia are an important target for anti-inflammatory activities of resveratrol in the brain.

Pediatr Neurol. 2008 Jan;38(1):20-6. PMID: 20361959


Oats contain avenanthramides which inhibit proliferation of human colon cancer cell lines in vitro.

A high intake of whole grain foods is associated with reduced risk of colon cancer, but the mechanism underlying this protection has yet to be elucidated. Chronic inflammation and associated cyclooxygenase-2 (COX-2) expression in the colon epithelium are causally related to epithelial carcinogenesis, proliferation, and tumor growth. We examined the effect of avenanthramides (Avns), unique polyphenols from oats with anti-inflammatory properties, on COX-2 expression in macrophages, colon cancer cell lines, and on proliferation of human colon cancer cell lines. We found that Avns-enriched extract of oats (AvExO) had no effect on COX-2 expression, but it did inhibit COX enzyme activity and prostaglandin E(2) (PGE(2)) production in lipopolysaccharide-stimulated mouse peritoneal macrophages. Avns (AvExO, Avn-C, and the methylated form of Avn-C (CH3-Avn-C)) significantly inhibited cell proliferation of both COX-2-positive HT29, Caco-2, and LS174T, and COX-2-negative HCT116 human colon cancer cell lines, CH3-Avn-C being the most potent. However, Avns had no effect on COX-2 expression and PGE(2) production in Caco-2 and HT29 colon cancer cells. These results indicate that the inhibitory effect of Avns on colon cancer cell proliferation may be independent of COX-2 expression and PGE(2) production. Thus, Avns might reduce colon cancer risk through inhibition of macrophage PGE(2) production and non-COX-related antiproliferative effects in colon cancer cells. Interestingly, Avns had no effect on cell viability of confluence-induced differentiated Caco-2 cells, which display the characteristics of normal colonic epithelial cells. Our results suggest that the consumption of oats and oat bran may reduce the risk of colon cancer not only because of their high fiber content but also due to Avns, which attenuate proliferation of colonic cancer cells.

Nutr Cancer. 2010;62(8):1007-16. PMID: 21058188


Red wine polyphenols inhibit human breast cancer cells.

Breast cancer (one of the most common malignancy in Western societies), as well as esophagus, stomach, lung, bladder, and prostate cancer, depend on environmental factors and diet for growth and evolution. Dietary micronutriments have been proposed as effective inhibitory agents for cancer initiation, progression, and incidence. Among them, polyphenols, present in different foods and beverages, have retained attention in recent years. Red wine is a rich source of polyphenols, and their antioxidant and tumor arresting effects have been demonstrated in different in vitro and in vivo systems. In the present study, we have measured the antiproliferative effect of red wine concentrate, its total polyphenolic pool, and purified catechin, epicatechin, quercetin, and resveratrol, which account for more than 70% of the total polyphenols in red wine, on the proliferation of hormone sensitive (MCF7, T47D) and resistant (MDA-MB-231) breast cancer cell lines. Our results indicate that polyphenols, at the picomolar or the nanomolar range, decrease cell proliferation in a dose- and a time-dependant manner. In hormone sensitive cell lines, a specific interaction of each polyphenol with steroid receptors was observed, with IC(50)s lower than previously described. Interaction of polyphenols with steroid receptors cannot fully explain their inhibitory effect on cell proliferation. In addition, discrete antioxidant action on each cell line was detected under the same concentrations, both by modifying the toxic effect of H(2)O(2), and the production of reactive oxygen species (ROS), after phorbol ester stimulation. Our results suggest that low concentrations of polyphenols, and consecutively, consumption of wine, or other polyphenol-rich foods and beverages, could have a beneficial antiproliferative effect on breast cancer cell growth.

J Cell Biochem. 2000 Jun 6;78(3):429-41. PMID: 10861841


Resveratrol or a combination of resveratrol and quercetin, in concentrations equivalent to that present in red wines, are effective inhibitors of oral squamous carcinoma cell (SCC-25) growth and proliferation.

Resveratrol and quercetin are polyphenols which have been detected in significant amounts in green vegetables, citrus fruits and red grape wines. Beneficial effects attributed to these compounds include anti-inflammatory, antiviral and antitumor properties. The effect of resveratrol and quercetin on growth of human oral cancer cells is unknown. Resveratrol and quercetin, in concentrations of 1 to 100 microM, were incubated in triplicates with human oral squamous carcinoma cells SCC-25 in DMEM-HAM's F-12 supplemented with fetal calf serum and antibiotics in an atmosphere of 5% CO2 in air at 37 degrees C for 72 h. Cell growth was determined by counting the number of viable cells with a hemocytometer. Cell proliferation was measured by means of incorporation of [3H]thymidine in nuclear DNA. Resveratrol at 10 and 100 microM induced significant dose-dependent inhibition in cell growth as well as in DNA synthesis. Quercetin exhibited a biphasic effect, stimulation at 1 and 10 microM, and minimal inhibition at 100 microM in cell growth and DNA synthesis. Combining 50 microM of resveratrol with 10, 25 and 50 microM of quercetin resulted in a gradual and significant increase in the inhibitory effect of quercetin on cell growth and DNA synthesis. We conclude that resveratrol or a combination of resveratrol and quercetin, in concentrations equivalent to that present in red wines, are effective inhibitors of oral squamous carcinoma cell (SCC-25) growth and proliferation, and warrant further investigation as cancer chemopreventive agents.

Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):32-7. PMID: 10211549


Resveratrol has antioxidant and anti-inflammatory effects in airway disease.

Respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are a significant and increasing global health problem. These diseases are characterized by airway inflammation, which develops in response to various stimuli. In asthma, inflammation is driven by exposure to a variety of triggers, including allergens and viruses, which activate components of both the innate and acquired immune responses. In COPD, exposure to cigarette smoke is the primary stimulus of airway inflammation. Activation of airway inflammatory cells leads to the release of excessive quantities of reactive oxygen species (ROS), resulting in oxidative stress. Antioxidants provide protection against the damaging effects of oxidative stress and thus may be useful in the management of inflammatory airways disease. Resveratrol, a polyphenol that demonstrates both antioxidative and anti-inflammatory functions, has been shown to improve outcomes in a variety of diseases, in particular, in cancer. We review the evidence for a protective role of resveratrol in respiratory disease. Mechanisms of resveratrol action that may be relevant to respiratory disease are described. We conclude that resveratrol has potential as a therapeutic agent in respiratory disease, which should be further investigated.

Antioxid Redox Signal. 2010 Nov 15;13(10):1535-48. PMID: 20214495


Resveratrol mobilizes endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage which may have chemoprentive

Plant polyphenols are important components of human diet, and a number of them are considered to possess chemopreventive and therapeutic properties against cancer. They are recognized as naturally occurring anti-oxidants but also act as pro-oxidants catalyzing DNA degradation in the presence of metal ions such as copper. The plant polyphenol resveratrol confers resistance to plants against fungal agents and has been implicated as a cancer chemopreventive agent. Of particular interest is the observation that resveratrol has been found to induce apoptosis in cancer cell lines but not in normal cells. Over the last few years, we have shown that resveratrol is capable of causing DNA breakage in cells such as human lymphocytes. Such cellular DNA breakage is inhibited by copper specific chelators but not by iron and zinc chelating agents. Similar results are obtained by using permeabilized cells or with isolated nuclei, indicating that chromatin-bound copper is mobilized in this reaction. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Therefore, cancer cells may be more subject to electron transfer between copper ions and resveratrol to generate reactive oxygen species responsible for DNA cleavage. The results are in support of our hypothesis that anti-cancer mechanism of plant polyphenols involves mobilization of endogenous copper and the consequent pro-oxidant action. Such a mechanism better explains the anti-cancer effects of resveratrol, as it accounts for the preferential cytotoxicity towards cancer cells.

Pharm Res. 2010 Jun;27(6):979-88. Epub 2010 Jan 30. PMID: 20119749


Resveratrol induces programmed cell death and cell cycle arrest of human bladder cancer cells.

Resveratrol, a naturally occurring polyphenolic antioxidant compound present in grapes and red wine, has been reported to hold various biochemical responses. In this preliminary study, we evaluate the chemopreventive potential of resveratrol against bladder cancer and its mechanism of action. Treatment of bladder cancer cells with resveratrol resulted in a significant decrease in cell viability. Resveratrol induced apoptosis through the modulation of Bcl-2 family proteins and activation of caspase 9 and caspase 3 followed by poly(ADP-ribose) polymerase degradation. Treatment with resveratrol led to G(1) phase cell cycle arrest in T24 cells by activation of p21 and downregulation of cyclin D1, cyclin-dependent kinase 4, and phosphorylated Rb. Resveratrol also inhibited the phosphorylation of Akt, whereas the phosphorylation of p38 MAPK was enhanced. In addition, resveratrol treatment decreased the expression of vascular endothelial growth factor and fibroblast growth factor-2, which might contribute to the inhibition of tumor growth on the bladder cancer xenograft model. These findings suggest that reveratrol could be an important chemoprevention agent for bladder cancer.

Cancer Sci. 2010 Feb;101(2):488-93. Epub 2009 Oct 27. PMID: 20028382


Antioxidant extracts from potatoes inhibit the proliferation of human colon and liver cancer cells.

Antioxidant extracts from 5 potato lines were evaluated for antioxidant activity, total phenolics, chlorogenic acid, anthocyanin content, and in vitro anticancer capacity. Analysis showed that Mexican wild species S. pinnatisectum had the highest antioxidant activity, total phenolic, and chlorogenic acid content. The proliferation of colon cancer and liver cancer cells was significantly inhibited by potato antioxidant extracts. The highest antiproliferative activity was observed in extracts of S. pinnatisectum and the lowest in Northstar. An inverse correlation was found between total phenolics and the EC(50) of colon cancer cell (R(2) = 0.9303), as well as liver cancer cell proliferation (R(2) = 0.8992). The relationship between antioxidant activity and EC(50) of colon cancer/liver cancer cell proliferation was significant (R(2) = 0.8144; R(2) = 0.956, respectively). A significant difference in inhibition of cancer cells (P

Nutr Cancer. 2011 Sep 2. Epub 2011 Sep 2. PMID: 21888504


"Curcumin and Liver Cancer: A Review."

Primary liver cancer, also known as hepatocellular carcinoma (HCC), is one of the most lethal cancers having worldwide prevalence. Although most HCC cases are reported in the developing countries of Asia and Africa, there has been an alarming increase in HCC cases in Western Europe as well as United States. Chronic liver diseases, viral hepatitis, alcoholism as well as dietary carcinogens, such as aflatoxins and nitrosoamines, contribute to HCC. Liver transplantation as well as surgical resection at best offer limited treatment options. Thus, there exists a critical need to investigate and evaluate possible alternative chemopreventive and therapeutic strategies which may be effective in the control of liver cancer. HCC, most often, develops and progresses in a milieu of oxidative stress and inflammation. Phytochemicals, such as dietary polyphenols endowed with potent antioxidant as well as anti-inflammatory properties, provide a suitable alternative in affording alleviation of HCC. Curcumin, the principal polyphenolic curcuminoid, obtained from the turmeric rhizome Curcuma longa has long been used to cure several chronic ailments, such as neoplastic and neurodegenerative diseases. Studies suggest that curcumin may have antitumor, antioxidant, and anti-inflammatory properties. This article reviews the effects of curcumin in preclinical in vitro and in vivo models of HCC with particular emphasis to its antioxidant, apoptotic and anti-inflammatory effects as well as involvement in various molecular signaling mechanisms. This review also discusses potential challenges involved in the use of curcumin in HCC, such as bioavailability, pharmacokinetics, drug delivery as well as paucity of clinical studies.

Curr Pharm Biotechnol. 2011 Apr 5. Epub 2011 Apr 5. PMID: 21466422


"Curcumin nanoparticles improve the physicochemical properties of curcumin and effectively enhance its antioxidant and antihepatoma activities."

Curcumin (CUR), a natural polyphenol isolated from tumeric ( Curcuma longa ), has been documented to possess antioxidant and anticancer activities. Unfortunately, the compound has poor aqueous solubility, which results in poor bioavailability following high doses by oral administration. To improve the solubility of CUR, we developed a novel curcumin nanoparticle system (CURN) and investigated its physicochemical properties as well as its enhanced dissolution mechanism. Our results indicated that CURN improved the physicochemical properties of CUR, including a reduction in particle size and the formation of an amorphous state with hydrogen bonding, both of which increased the drug release of the compound. Moreover, in vitro studies indicated that CURN significantly enhanced the antioxidant and antihepatoma activities of CUR (P

J Agric Food Chem. 2010 Jun 23 ;58(12):7376-82. PMID: 20486686


"Resveratrol inhibits tumor necrosis factor-alpha-mediated matrix metalloproteinase-9 expression and invasion of human hepatocellular carcinoma cells."

Resveratrol is an active polyphenol found in red wine that has anti-cancer effects, but the molecular mechanisms of resveratrol on tumor invasion inhibition have not been well documented. The aim of this study was to elucidate the effects of resveratrol on invasion ability of human hepatocellular carcinoma cells and TNF-alpha-mediated MMP-9 expression. The expression activity of MMP-9 was measured by zymography, RT-PCR and western blot analysis. The expression of NF-kappa B was measured by EMSA and western blot analysis. TNF-alpha induced the MMP-9 expression in HepG2 cells. Resveratrol significantly inhibited TNF-alpha-mediated MMP-9 expression in HepG2 cells. NF-kappa B inhibitor induced a marked reduction in MMP-9 expression, and it suggested that NF-kappa B could play an important role in TNF-alpha-mediated MMP-9 expression. Furthermore, resveratrol significantly suppressed TNF-alpha-mediated NF-kappa B expression and invasion of HepG2 cells. Our results showed that resveratrol inhibited TNF-alpha-mediated MMP-9 expression and invasion of human hepatocellular carcinoma cells. The inhibitory effects are partly associated with the downregulation of the NF-kappa B signaling pathway.

Biomed Pharmacother. 2008 Jul-Aug;62(6):366-72. Epub 2007 Oct 22. PMID: 17988825


Solanum nigrum L. polyphenolic extract inhibits hepatocarcinoma cell growth.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rapidly progressive cancer with poor prognosis. However, there have been no significant new developments in treating liver cancer. To search for an effective agent against HCC progression, we prepared a polyphenolic extract of Solanum nigrum L. (SNPE), a herbal plant indigenous to Southeast Asia and commonly used in oriental medicine, to evaluate its inhibitive effect on hepatocarcinoma cell growth. The growth inhibition of HepG2 cells in vitro and in vivo was determined in the presence of SNPE.RESULTS: We found 1 µg mL(-1) SNPE-fed mice showed decreased tumor weight and tumor volume by 90%. Notably, 2 µg mL(-1) SNPE resulted in almost complete inhibition of tumor weight as well as tumor volume. In line with this notion, SNPE reduced the viability of HepG(2) cells in a dose-dependent manner. HepG(2) cells were arrested in the G(2)/M phase of the cell cycle; meanwhile, the protein levels of cell CDC25A, CDC25B, and CDC25C were clearly reduced. Moreover, sub-G(1) phase accumulation and caspases-3, 8, and 9 cleavages were induced by SNPE.CONCLUSION: This study shows that SNPE is a potent agent for HCC treatment through targeting G(2)/M arrest and apoptosis induction, achieving cell growth inhibition.

J Sci Food Agric. 2011 Jan 15 ;91(1):178-85. Epub 2010 Sep 17. PMID: 20853273


Quercetin exhibits an inhibitory effect in a human hepatoma cell line.

Dietary polyphenols have been associated with the reduced risk of chronic diseases such as cancer, but the precise underlying mechanism of protection remains unclear. The aim of this study was to investigate the effect of quercetin on the activation of the apoptotic pathway in a human hepatoma cell line (HepG2). Treatment of cells for 18 h with quercetin induced cell death in a dose-dependent manner; however, a shorter treatment (4 h) had no effect on cell viability. Incubation of HepG2 cells with quercetin for 18 h induced apoptosis by the activation of caspase-3 and -9, but not caspase-8. Moreover, this flavonoid decreased the Bcl-xL:Bcl-xS ratio and increased translocation of Bax to the mitochondrial membrane. A sustained inhibition of the major survival signals, Akt and extracellular regulated kinase (ERK), also occurred in quercetin-treated cells. These data suggest that quercetin may induce apoptosis by direct activation of caspase cascade (mitochondrial pathway) and by inhibiting survival signaling in HepG2.

J Nutr. 2006 Nov ;136(11):2715-21. PMID: 17056790


"Curcumin: A Potential Neuroprotective Agent in Parkinson's Disease."

Parkinson's disease (PD) is an age-associated neurodegenerative disease clinically characterized as a movement disorder. The motor symptoms in PD arise due to selective degeneration of dopaminergic neurons in the substantia nigra of the ventral midbrain thereby depleting the dopamine levels in the striatum. Most of the current pharmacotherapeutic approaches in PD are aimed at replenishing the striatal dopamine. Although these drugs provide symptomatic relief during early PD, many patients develop motor complications with long-term treatment. Further, PD medications do not effectively tackle tremor, postural instability and cognitive deficits. Most importantly, most of these drugs do not exhibit neuroprotective effects in patients. Consequently, novel therapies involving natural antioxidants and plant products/molecules with neuroprotective properties are being exploited for adjunctive therapy. Curcumin is a polyphenol and an active component of turmeric (Curcuma longa), a dietary spice used in Indian cuisine and medicine. Curcumin exhibits antioxidant, anti-inflammatory and anti-cancer properties, crosses the blood-brain barrier and is neuroprotective in neurological disorders. Several studies in different experimental models of PD strongly support the clinical application of curcumin in PD. The current review explores the therapeutic potential of curcumin in PD.

Curr Pharm Des. 2012 Jan 1. Epub 2012 Jan 1. PMID: 22211691


The soy isoflavone genistein appears to repress human breast cancer cells.

Mammary stem cells are undifferentiated epithelial cells which initiate mammary tumors and render them resistant to anticancer therapies, when deregulated. Diets rich in fruits and vegetables are implicated in breast cancer risk reduction, yet underlying mechanisms are poorly understood. Here, we addressed whether dietary factors selectively target mammary epithelial cells that display stem-like/progenitor subpopulations with previously recognized tumor-initiating potential. Using estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 human breast cancer cell lines and freshly isolated epithelial cells from MMTV-Wnt-1 transgenic mouse mammary tumors, we demonstrate that sera of adult mice consuming soy isoflavone genistein (GEN) or blueberry (BB) polyphenol-containing diets alter the population of stem-like/progenitor cells, as measured by their functional ability to self-renew and form anchorage-independent spheroid cultures in vitro at low frequency (1-2%). Serum effects on mammosphere formation were dose-dependently replicated by GEN (40 nM>2 μM) and targeted the basal stem-like CD44(+)/CD24(-)/ESA(+) and the luminal progenitor CD24(+) subpopulations in MDA-MB231 and MCF-7 cells. GEN inhibition of mammosphere formation was mimicked by the Akt inhibitor perifosine and was associated with enhanced tumor suppressor PTEN expression. By contrast, a select mixture of BB phenolic acids was only active in MDA-MD-231 cells and its CD44(+)/CD24(-)/ESA(+) subpopulation, and this activity was independent of induction of PTEN expression. These findings delineate a novel and selective function of distinct dietary factors in targeting stem/progenitor cell populations in estrogen receptor-dependent and -independent breast cancers.

Carcinogenesis. 2012 Jan 4. Epub 2012 Jan 4. PMID: 22219179


Curcumin has a synergistic antitumor effect in combination with docetaxel against lung cancer.

Curcumin (Cum), the principal polyphenolic curcuminoid, obtained from the turmeric rhizome Curcuma longa, is recently reported to have potential antitumor effects in vitro and in vivo. Docetaxel (Doc) is considered as first-line chemotherapy for the treatment of non-small cell lung cancer. Here we report for the first time that Cum could synergistically enhance the in vitro and in vivo antitumor efficacy of Doc against lung cancer. In the current study, combination index (CI) is calculated in both in vitro and in vivo studies to determine the interaction between Cum and Doc. In the in vitro cytotoxicity test, media-effect analysis clearly indicated a synergistic interaction between Cum and Doc in certain concentrations. Moreover, in vivo evaluation further demonstrated the superior anticancer efficacy of Cum + Doc compared with Doc alone by intravenous delivery in an established A549 transplanted xenograft model. Results showed that Cum synergistically increased the efficacy of Doc immediately after 4 days of the initial treatment. Additionally, simultaneous administration of Cum and Doc showed little toxicity to normal tissues including bone marrow and liver at the therapeutic doses. Therefore, in vitro and in vivo evaluations demonstrated the satisfying synergistic antitumor efficacy of Cum and Doc against lung cancer and the introduction of Cum in traditional chemotherapy is a most promising way to counter the spread of non-small cell lung cancer.

Acta Biochim Biophys Sin (Shanghai). 2012 Feb ;44(2):147-53. Epub 2011 Nov 29. PMID: 22126905


Curcumin may have positive epigenetic effects in high prostate cancer.

Curcumin (CUR), a major bioactive polyphenolic component from turmeric curry, Curcuma longa, has been shown to be a potent anti-cancer phytochemical with well-established anti-inflammatory and anti-oxidative stress effects. Chromatin remodeling-related epigenetic regulation has emerged as an important mechanism of carcinogenesis, chemoprevention, and chemotherapy. CUR has been found to inhibit histone acetyltransferase activity, and it was also postulated to be a potential DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitor. In this study, we show that when human prostate LNCaP cells were treated with CUR, it led to demethylation of the first 14 CpG sites of the CpG island of the Neurog1 gene and restored the expression of this cancer-related CpG-methylation epigenome marker gene. At the protein level, CUR treatment had limited effects on the expression of epigenetic modifying proteins MBD2, MeCP2, DNMT1, and DNMT3a. Using ChIP assay, CUR decreased MeCP2 binding to the promoter of Neurog1 dramatically. CUR treatment showed different effects on the protein expression of HDACs, increasing the expression of HDAC1, 4, 5, and 8 but decreasing HDAC3. However, the total HDAC activity was decreased upon CUR treatment. Further analysis of the tri-methylation of histone 3 at lysine 27 (H3K27me3) showed that CUR decreased the enrichment of H3K27me3 at the Neurog1 promoter region as well as at the global level. Taken together, our present study provides evidence on the CpG demethylation ability of CUR on Neurog1 while activating its expression, suggesting a potential epigenetic modifying role for this phytochemical compound in human prostate cancer cells.

AAPS J. 2011 Dec ;13(4):606-14. Epub 2011 Sep 22. PMID: 21938566


Curcumin inhibits multi-drug resistant leukemia cells.

The anti-cancer activities of curcumin (CUR), a polyphenol derived from the plant Curcuma longa, has been extensively studied. In the present study, we found that CUR displayed anti-multidrug-resistant (MDR) activity in K562/A02 cells. A short-time treatment with CUR sufficiently and equally induced DNA damage, decreased cell viability, and triggered apoptosis in parent K562 and MDR K562/A02 cells. The short-time treatment with CUR also caused decrease of pro-caspase 3 in both cell lines and decrease of pro-caspase 9, increase of PARP cleavage and the ratio of Bax/Bcl-xL in MDR K562/A02 cells. Further experiment revealed that CUR was capable of down-regulating P-glycoprotein in MDR K562/A02 cells. Moreover, we observed that Cu(2+) enhanced CUR-mediated apoptosis which was blocked by antioxidants N-acetyl-cysteine and catalase. In summary, the short-time treatment with CUR sufficiently induced DNA damage, decreased cell viability and triggered apoptosis in MDR K562/A02 cells and Cu(2+) enhanced CUR-mediated apoptosis which due to reactive oxygen species generation.

Mol Cell Biochem. 2012 Jan ;360(1-2):253-60. Epub 2011 Sep 22. PMID: 21938404

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