Metformin inhibits the tumor-promoting effect of low-dose resveratrol, and enhances the anti-tumor activity of high-dose resveratrol by increasing its reducibility in triple negative breast cancer.

Resveratrol, a natural antioxidant that maintains better bioactivity under hypoxia, has anti-tumor effects, but its underlying mechanism is controversial and the effect on Triple-negative breast cancer (TNBC) remains unclear. Herein, we investigated the anti-TNBC mechanism of resveratrol under a mimic hypoxic tumor microenvironment and explored a method of combining metformin to improve the therapeutic effect. The results showed an inverted "U" shaped relationship between the cell viability and resveratrol concentrations. Low concentrations of resveratrol (LRes) promoted proliferation and migration in MDA-MB-231 cells by activating JAK3/STAT3 signaling pathway, while high concentrations of resveratrol (HRes) inhibited cell growth and induced both autophagy and apoptosis through MAPK signaling pathway. Meanwhile, HRes treatment resulted in the up-regulation of antioxidant-related genes SOD3 and FAM213B, the increase of catalase activity and NAD(P)H level, which leading to a reducing microenvironment in cells. Notably, metformin could inhibit the proliferation and migration induced by LRes, whereas promote apoptosis induced by HRes. Moreover, metformin enhanced the reducing environment via further increasing the catalase activity and NAD(P)H level. These findings conclude the anti-TNBC mechanism of HRes should be attributed to its antioxidant activity and metformin enhances its reducibility. Metformin combined with resveratrol exerts a synergistic therapeutic effect on TNBC and effectively prevents tumor progression.