Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells

Bernhard, David; Tinhofer, Ingeborg; Tonko, Martin; Hubl, H.; Ausserlechner, Michael J.; Greil, Richard; Kofler, Reinhard; Csordás, Adam

doi:10.1038/sj.cdd.4400719

Cited by 143 publications

(120 citation statements)

References 53 publications

(55 reference statements)

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“…Resveratrol also has direct cytostatic (6, 7) or cytotoxic effects (4,10,12,15). The later effect can be mediated by apoptosis through activation of both the extrinsic and the intrinsic pathways to caspase activation, oncoproteins, and kinase pathways (4,10,12,15,24). Mechanisms responsible for the resveratrol chemopreventive and chemosensitization properties are poorly known in tumor cells, but evidence indicates that resveratrol uptake and the cancer microenvironment plasma membrane play a key role in these processes.…”

Section: Discussionmentioning

confidence: 99%

“…8,9) and/or its ability to trigger tumor cell death by apoptosis (4,(10)(11)(12). There is also compelling evidence that resveratrol can sensitize tumor cells to various anticancer drugs (13,14) and cytokines such as TRAIL (11), possibly because of the clustering of death receptors in detergent-resistant membranes (DRM) known as lipid rafts (4,11,15).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…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.…”

mentioning

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

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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“…Resveratrol has been proposed as a potential chemothera- Figure 3A and 3B), but resveratrol mainly arrests cells in the G 1 and S phases [21][22][23][24] . This result suggests that the simple functional group substitution of a natural compound can change its anti-cancer activity.…”

Section: Discussionmentioning

confidence: 99%

4′-Chloro-3,5-dihydroxystilbene, a resveratrol derivative, induces lung cancer cell death

Tsai

Shee

et al. 2010

Acta Pharmacol Sin

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Aim: To examine the antitumor effect of 4′-chloro-3,5-dihydroxystilbene, a resveratrol derivative, on lung adenocarcinoma A549 cells. Methods: The cytotoxic IC 50 was determined by direct cell counting. Flow cytometry, monodansylcadaverine (MDC) staining, transfection, Western blot and a proteasome activity assay were used to study the cellular mechanism of 4′-chloro-3,5-dihydroxystilbene. A xenograft nude mouse model was used to analyze the antitumor effect in vivo. Results: 4′-Chloro-3,5-dihydroxystilbene induced a rapid and persistent increase in the intracellular reactive oxygen species in the cells, but the cell death could not be inhibited by two antioxidant agents. The derivative caused sub-G 1 formation, a decrease in the mitochondria membrane potential and poly (ADP-ribose) polymerase degradation, and the caspase inhibitor Z-VAD-FMK could partially prevent cell death. It also induced a significant increase in intracellular acidic vacuoles, LC3-II formation and intracellular GFP-LC3 aggregation. An autophagic inhibitor partially reversed cell death. Additionally, 4′-chloro-3,5-dihydroxystilbene induced the accumulation of ubiquitinated conjugates and inhibited proteasome activity in cells. In an in vivo study, 4′-chloro-3,5-dihydroxystilbene retarded tumor growth in nude mice. Conclusion: These data suggest that the resveratrol derivative 4′-chloro-3,5-dihydroxystilbene could be developed as an anti-tumor compound.

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Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells

Cited by 143 publications

References 53 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

4′-Chloro-3,5-dihydroxystilbene, a resveratrol derivative, induces lung cancer cell death

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