Resveratrol induces DNA damage in colon cancer cells by poisoning topoisomerase II and activates the ATM kinase to trigger p53-dependent apoptosis

[Display omitted] •Resveratrol induces DNA damage and p53-dependent apoptosis in colon cancer cells.•Formation of DNA damage does not rely on a pro-oxidant effect of resveratrol.•Resveratrol is not a topoisomerase I inhibitor or a DNA intercalating agent.•DNA damage is the consequence of type II topoisomerase poisoning by resveratrol.•The Ataxia Telangiectasia Mutated (ATM) kinase is required to activate p53. 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 γ-H2AX foci in 50% of cells after a 24h treatment with 25μM 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.