Resveratrol Decreases Rad51 Expression and Sensitizes Cisplatin‑resistant MCF‑7 Breast Cancer Cells

Resveratrol (RES), a polyphenol compound with anti-proliferative properties, has been previously evaluated for its beneficial effects against a variety of tumour cells. The current study elucidated the means by which RES enhances the anti-proliferative effects of cisplatin (CIS) on MCF-7 cells, focusing on the inhibitory effects on DNA repair of double-strand breaks (DSBs). Chemoresistant MCF-7 cells (MCF-7R) were generated by continuous exposure to low concentrations of CIS (10 mu M CIS-IC40) during 5 passages, with the IC50 value increasing similar to 3-fold. Using an MTT assay, we estimated the changes in IC50 for CIS in MCF-7, T47-D, MDA-MB-231 and MCF-7R cells in the presence of RES. The relative transcript level of Nbs-1, Mre-11 and Rad-50 genes was assessed using RT-qPCR analysis. Rad51 and H2AX [pSer139] protein expression was determined by western blot analysis. RES at 50 and 100 mu M significantly enhanced the anti-proliferative effects of CIS in both MCF-7 and MCF-7R cells, decreasing the IC50 values for CIS to one-tenth and one-sixth, respectively. A total of 100 mu M RES decreased the relative transcript levels of homologous recombination (HR) initiation complex components and the Rad51 protein level in MCF-7 and MCF-7R cells. After 48 h of CIS DNA damage, the levels of Rad51 protein increased, but this effect was inhibited by 100 mu M RES. RES also maintained serine 139 phosphorylation of histone H2AX, suggesting that RES prevents the repair of DSBs. It was observed that RES exerts an antagonistic effect over CIS on the activation of Rad51 and sustained phosphorylation of H2AX. The results suggest that RES in combination with DNA damage-based therapy has potential as a strategy to overcome resistance and provide much safer and more effective treatment for breast cancer.