Resveratrol reduces the hypoxia-induced resistance to doxorubicin in breast cancer cells

Abstract

Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is known to enhance the cyto-toxicity of the anticancer drug doxorubicin. On the other hand, breast cancer MCF-7 cells acquire resistance to doxorubicin under hypoxic conditions. In this study, we investigated the effect of resveratrol on hypoxia-induced resistance to doxorubicin in MCF-7 cells. Resver-atrol and its derivative 3,5-dihydroxy-4′-methoxy-trans-stilbene, but not 3,5-dimethoxy-4′-hydroxy-trans-stilbene, cancelled hypoxia-induced resistance to doxorubicin at a concentration of 10 mm. Carbonyl reductase 1 (CBR1) catalyzes the conversion of doxorubicin to its metabolite doxorubicinol, which is much less effective than doxorubicin. Hypoxia increased the expression of CBR1 at both mRNA and protein levels, and knockdown of CBR1 inhibited hypoxia-induced resistance to doxorubicin in MCF-7 cells. Knockdown of hypoxia-inducible factor (HIF)-1a repressed the hypoxia-induced expression of CBR1. Resveratrol repressed the expression of HIF-1a protein, but not HIF-1a mRNA, and decreased hypoxia-activated HIF-1 activity. Resveratrol repressed the hypoxia-induced expression of CBR1 at both mRNA and protein levels. Likewise, 3,5-dihydroxy-4′-methoxy-trans-stilbene decreased the hypoxia-induced expression of CBR1 protein, but not 3,5-dimethoxy-4′-hydroxy-trans-stilbene. Furthermore, resveratrol decreased the expression of HIF-1a protein even in the presence of the proteasome inhibitor MG132 in hypoxia. Theses results indicate that in MCF-7 cells, HIF-1a-increased CBR1 expression plays an important role in hypoxia-induced resistance to doxorubicin and that resveratrol and 3,5-dihydroxy-4′-methoxy-trans-stilbene decrease CBR1 expression by decreasing HIF-1a protein expression, perhaps through a proteasome-independent pathway, and consequently repress hypoxia-induced resistance to doxorubicin.