Journal
TOXICOLOGY IN VITRO
Volume 29, Issue 5, Pages 1156-1165Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2015.04.015
Keywords
Resveratrol; p53; Apoptosis; DNA damage; Colon cancer; Topoisomerase II
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Funding
- FSR (Fonds Speciaux de Recherche, UCL, Belgium)
- FNRS (Fonds Nationaux de la Recherche Scientifique, Belgium)
- FNRS-FRIA (Belgium)
- FNRS-TELEVIE (Belgium)
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Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenol synthesized by various plants such as grape vine. Resveratrol (RSV) is a widely studied molecule, largely for its chemopreventive effect in different mouse cancer models. We propose a mechanism underlying the cytotoxic activity of RSV on colon cancer cells. Our data show that resveratrol induces apoptosis, as observed by the cleavage of PARP-1 and chromatin condensation. We show that the tumor suppressor p53 is activated in response to RSV and participates to the apoptotic process. Additionally, we show that HCT-116 p53 wt colon carcinoma cells are significantly more sensitive than HCT-116 p53-/- cells to RSV. RSV induces DNA damage including double strand breaks, as evidenced by the presence of multiple gamma-H2AX foci in 50% of cells after a 24 h treatment with 25 mu M RSV. The formation of DNA damage does not appear to rely on a pro-oxidant effect of the molecule, inhibition of topoisomerase I, or DNA intercalation. Rather, we show that DNA damage is the consequence of type II topoisomerase poisoning. Exposure of HCT-116 cells to RSV leads to activation of the Ataxia Telangiectasia Mutated (ATM) kinase, and ATM is required to activate p53. (C) 2015 Elsevier Ltd. All rights reserved.
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