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.