Resveratrol as a Chemopreventive Agent: A Promising Molecule for Fighting Cancer

Delmas, Dominique; Lançon, Allan; Colin, Didier; Jannin, Brigitte; Latruffe, Norbert

doi:10.2174/138945006776359331

Cited by 347 publications

(231 citation statements)

References 219 publications

(358 reference statements)

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“…Resveratrol (trans-3,4 0 ,5-trihydroxystilbene), a wine grape microcomponent, may be one of the most efficient of these polyphenols (1) in that it could prevent the occurrence of vascular diseases, neurodegenerative processes, and some malignant tumors (see for review ref. 2). These chemopreventive properties are supported by observations at the cellular and molecular levels (3)(4)(5) and reinforce the interest in grape products and dietary supplements for cancer therapy.…”

Section: Introductionsupporting

confidence: 52%

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

Colin

Limagne²,

Jeanningros³

et al. 2011

Cancer Prevention Research

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trans-Resveratrol has been proposed to prevent tumor growth and to sensitize cancer cells to anticancer agents. Polyphenol entry into the cells has remained poorly understood. Here, we show that [ 3 H]-resveratrol enters colon cancer cells (SW480, SW620, HT29) and leukemia U937 cells through a monensin (5-20 mmol/L) -sensitive process that suggests clathrin-independent endocytosis. Uptake of the molecule can be prevented by methyl-b-cyclodextrin (2-12 mg/mL), nystatin (12 ng/mL), and filipin (1 mg/mL), which all disrupt plasma membrane lipid rafts. Accordingly, radiolabeled resveratrol accumulates in sphingomyelin-and cholesterol-enriched cell fractions. Interestingly, extracellular signalregulated kinases (ERK), c-Jun NH 2 -terminal kinases (JNK), and Akt also accumulate in lipid rafts on resveratrol exposure (IC 50 at 48 h % 30 mmol/L in SW480 and U937 cells). In these rafts also, resveratrol promotes the recruitment, by the integrin a V b 3 (revealed by coimmunoprecipitation with an anti-integrin a V b 3 antibody), of signaling molecules that include the FAK (focal adhesion kinase), Fyn, Grb2, Ras, and SOS proteins. Resveratrol-induced activation of downstream signaling pathways and caspase-dependent apoptosis is prevented by endocytosis inhibitors, lipid raft-disrupting molecules, and the integrin antagonist peptide arginine-glycine-aspartate (500 nmol/L). Altogether, these data show the role played by lipid rafts in resveratrol endocytosis and activation of downstream pathways leading to cell death.

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Section: Introductionsupporting

confidence: 52%

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

Colin

Limagne²,

Jeanningros³

et al. 2011

Cancer Prevention Research

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“…27 Resveratrol and some derivatives also possess cytostatic and cytotoxic effects in tumor cells in vitro. 2,[4][5][6]28,29 We recently developed acetylated forms of resveratrol 14 that still inhibit colon cancer cell proliferation and this acetylation can improve its cellular uptake.…”

Section: Discussionmentioning

confidence: 99%

Effects of resveratrol analogs on cell cycle progression, cell cycle associated proteins and 5fluoro‐uracil sensitivity in human derived colon cancer cells

Colin

Gimazane

Lizard

et al. 2009

Intl Journal of Cancer

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114

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Epidemiological studies suggested that trans-resveratrol, a wine grape component, could prevent malignant tumor development. This compound also demonstrated cytostatic and cytotoxic effects on tumor cells in vitro. To obtain trans-resveratrol derivatives with a better cellular uptake and enhanced antiproliferative effects, we synthesized a triacetate derivative as well as an oligomer, e-viniferin and its acetylated form, e-viniferin penta-acetate. We also obtained vineatrol, a wine grape shoot extract that associates several polyphenols that may act synergistically, including trans-resveratrol and e-viniferin. We show here that resveratrol triacetate and vineatrol are as efficient as trans-resveratrol in inducing the accumulation of human colon cancer cells in early S phase of the cell cycle. This effect is associated with a nuclear redistribution of cyclin A and the formation of a cyclin A/cyclindependent kinase 2 complex whose kinase activity is increased. In contrast, e-viniferin and its acetylated form do not demonstrate any significant activity on these cells when tested alone. Interestingly, resveratrol triacetate and vineatrol dramatically enhance 5-Fluoro-Uracil-mediated inhibition of colon cancer cell proliferation. Thus, acetylated derivatives of resveratrol have retained the cytostatic and cytotoxic activities of the parental molecule and thus deserve to be tested as chemosensitizers in animal models. ' UICCKey words: colon cancer; cell cycle; polyphenols; resveratrol; vineatrol; chemosensitization Epidemiological studies suggested that the polyphenol resveratrol (trans-3,4 0 ,5-trihydroxystilbene) was one of the main wine grape components that protect from vascular diseases, neurodegenerative processes and cancers. 1 The ability of resveratrol to prevent the occurrence of carcinomas was related to the inhibition of tumor cell cycle 2,3 and induction of tumor cell death. 4,5 In addition, there is compelling in vitro evidence that trans-resveratrol behaves as a chemosensitizer when combined with cytotoxic drugs, 6 cytokines 7 and other polyphenols such as quercetin, apigenin and genistein. 8,9 Resveratrol is probably not the only bioactive compound present in the grape wine. Oligomers of resveratrol such as viniferins, were suggested to block the proliferation of several tumoral cell lines 10-12 and a vineatrol preparation containing both trans-resveratrol and e-viniferin exhibited a greater antiproliferative effect on malignant cell lines than each compound tested separately. 13,14 Lipophilic derivatives were obtained through esterification of the hydroxyl functions with aliphatic molecules, which improved their intestinal absorption and cell penetration. 15,16 Acetylation of the phenolic compounds could also favor their absorption, as demonstrated for catechins. 17 Acetylated derivatives of polyphenols can be found in natural sources such as plants. [18][19][20][21] The ability of acetylated polyphenols to promote tumor cell cycle arrest, death and to sensitize them to other anticancer agents remai...

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“…21, 22, and 50). Apart from considerations of the physiological relevance of resveratrol as a dietary constituent or as a potential therapeutic agent applied in higher doses in cancer chemoprevention or therapy (50), this compound represents an interesting model substance to provide further insight into the complex regulatory functions of SUR.…”

Section: Discussionmentioning

confidence: 99%

“…The equilibrium inhibition curves were analyzed using the logarithmic form of the Hill equation: y ϭ 100 Ϫ A(1 ϩ 10 nH(px Ϫ pIC50) ) Ϫ1 , where A denotes the extent of inhibition; n H is the Hill coefficient; IC 50 is the midpoint of the curve, with pIC 50 ϭ Ϫlog IC 50 ; and x is the concentration of the compound under study, with px ϭ Ϫlog x. The IC 50 values were converted into inhibition constants (K i ) by correcting for the presence of the radioligand (L) according to the Cheng-Prusoff equation:…”

Section: Methodsmentioning

confidence: 99%

Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner

Hambrock

Franz

Hiller

et al. 2007

Journal of Biological Chemistry

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Sulfonylurea receptors (SURs) constitute the regulatory subunits of ATP-sensitive K ؉ channels (K ATP channels). SUR binds nucleotides and synthetic K ATP channel modulators, e.g. the antidiabetic sulfonylurea glibenclamide, which acts as a channel blocker. However, knowledge about naturally occurring ligands of SUR is very limited. In this study, we show that the plant phenolic compound trans-resveratrol can bind to SUR and displace binding of glibenclamide. Electrophysiological measurements revealed that resveratrol is a blocker of pancreatic SUR1/ K IR 6.2 K ATP channels. We further demonstrate that, like glibenclamide, resveratrol induces enhanced apoptosis. This was shown by analyzing different apoptotic parameters (cell detachment, nuclear condensation and fragmentation, and activities of different caspase enzymes). The observed apoptotic effect was specific to cells expressing the SUR1 isoform and was not mediated by the electrical activity of K ATP channels, as it was observed in human embryonic kidney 293 cells expressing SUR1 alone. Enhanced susceptibility to resveratrol was not observed in pancreatic ␤-cells from SUR1 knock-out mice or in cells expressing the isoform SUR2A or SUR2B or the mutant SUR1(M1289T). Resveratrol was much more potent than glibenclamide in inducing SUR1-specific apoptosis. Treatment with etoposide, a classical inducer of apoptosis, did not result in SUR isoform-specific apoptosis. In conclusion, resveratrol is a natural SUR ligand that can induce apoptosis in a SUR isoform-specific manner. Considering the tissue-specific expression patterns of SUR isoforms and the possible effects of SUR mutations on susceptibility to apoptosis, these observations could be important for diabetes and/or cancer research.Sulfonylurea receptors (SURs) 2 are members of the ATPbinding cassette protein family (subfamily C). SURs are known to be the important regulatory subunits of ATP-sensitive K ϩ channels (K ATP channels). These channels are heteromeric complexes composed of four SUR subunits that surround a central pore formed by four subunits from the K IR 6.x family. K ATP channels found in various tissues exhibit distinct physiological and pharmacological properties because of the combination of different subunit isoforms (reviewed in Ref. 1). In addition to two nucleotide-binding domains, SUR possesses binding sites for synthetic K ATP channel modulators. The binding sites for blockers and openers are different, but they are linked via complex allosteric interactions (2, 3).Because of their nucleotide sensitivity, K ATP channels couple the energy metabolism of a cell to the membrane potential. This is important in the pancreatic ␤-cell, in which closure of K ATP channels triggers insulin secretion via membrane depolarization in response to changes in blood glucose levels (4 -6). K ATP channel-blocking drugs such as the sulfonylureas and the glinides can promote insulin secretion and are used in the treatment of diabetes type 2. Insulin secretion is also modulated and amplified by other pathways...

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Resveratrol as a Chemopreventive Agent: A Promising Molecule for Fighting Cancer

Cited by 347 publications

References 219 publications

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

Endocytosis of Resveratrol via Lipid Rafts and Activation of Downstream Signaling Pathways in Cancer Cells

Effects of resveratrol analogs on cell cycle progression, cell cycle associated proteins and 5fluoro‐uracil sensitivity in human derived colon cancer cells

Resveratrol Binds to the Sulfonylurea Receptor (SUR) and Induces Apoptosis in a SUR Subtype-specific Manner

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