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

Abstract

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...

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

“…In a similar manner, we have previously shown that lipid rafts play a role in clustering or aggregating surface receptors and adaptor molecules into membrane complexes at specific sites and are shown to be essential for initiating signaling from a number of receptors, particularly in the initiation of Fas-mediated apoptosis during resveratrol treatment (4). These microdomains sequester the polyphenol, as described recently for autocrine motility factor (AMF)/phosphoglucose isomerase (PGI)-paclitaxel (46), and therefore function as a platform that finely tunes up the tumor cell response to this agent, either directly by inducing cell-cycle arrest or cell death (47) or indirectly by sensitizing the cells to chemotherapeutic agents (11,15). This sensitization could involve the inhibition of the H þ -ATP synthase by resveratrol (48).…”

Anti-angiogenic effects of resveratrol in combination with 5-fluorouracil on B16 murine melanoma cells

“…Therefore, several studies have evaluated novel treatments or 5-FU combination treatments to overcome this drug resistance. Previous studies have demonstrated that co-treatment of cells with genistein and 5-FU reduces the proliferation of colon cancer cells more effectively compared with genistein or 5-FU alone (4), and the co-treatment of colon cancer cells with resveratrol and 5-FU inhibited cell growth more effectively compared with resveratrol or 5-FU alone (25). In the present study, the combination treatment of 5-FU and resveratrol was investigated in order to develop modalities to overcome drug resistance.…”

Use of Grape Polyphenols Against Carcinogenesis: Putative Molecular Mechanisms of Action Using In Vitro and In Vivo Test Systems

“…Some authors have suggested that resveratrol triacetate and vineatrol are efficient in inducing the accumulation of human colon cancer cells in the early S phase of the cell cycle. 24 This effect is associated with a nuclear redistribution of cyclin A and the formation of a cyclin A/cyclin-dependent kinase 2 complex whose kinase activity is increased. 24 Of particular importance, resveratrol triacetate and vineatrol dramatically enhance 5-fluoro-uracil-mediated inhibition of colon cancer cell proliferation.…”

“…24 This effect is associated with a nuclear redistribution of cyclin A and the formation of a cyclin A/cyclin-dependent kinase 2 complex whose kinase activity is increased. 24 Of particular importance, resveratrol triacetate and vineatrol dramatically enhance 5-fluoro-uracil-mediated inhibition of colon cancer cell proliferation. 24 The potential inhibitory effect of the resveratrol derivative on cell proliferation and the…”

“…24 Of particular importance, resveratrol triacetate and vineatrol dramatically enhance 5-fluoro-uracil-mediated inhibition of colon cancer cell proliferation. 24 The potential inhibitory effect of the resveratrol derivative on cell proliferation and the…”