Nicotinamide Overcomes Doxorubicin Resistance of Breast Cancer Cells through Deregulating SIRT1/Akt Pathway.

Abstract

Breast cancer is one of the leading causes of cancer deaths in female worldwide. Doxorubicin represents the most common chemotherapy for breast cancer, whereas side effects and development of resistance impede its effect on chemotherapy. Nicotinamide (NAM), serves as the sirtuins' inhibitor, effectively suppressing various types of cancer. However, the effects of NAM on drug resistance of breast cancer are need to be fully investigated. Breast cancer doxorubicin-resistant cells MCF-7/ADR and doxorubicin-sensitive cells MCF-7 were applied in this study. Cell proliferation was assessed by CCK8 and colony-forming assays. Cell migration was evaluated by scratch test and transwell assay while cell apoptosis was measured by TUNEL analysis. Expression levels of SIRT1, phosphate Akt (P-Akt, Ser-473) and Akt were measured using western blot analysis. The interrelation between SIRT1 and Akt was investigated by co-immunoprecipitation assay. Treatment of nicotinamide combined with doxorubicin effectively inhibited cell growth, suppressed cell migration, and promoted cell apoptosis of MCF7/ADR cells. Mechanistically, nicotinamide translocated SIRT1 from the cell nucleus to cytoplasm, dissociated the connection between SIRT1 and Akt, and consequently decreased expressions of SIRT1, and P-Akt, thereby inhibiting the growth of MCF7/ADR cells. Our results suggested that the value of nicotinamide is a potential therapeutic agent for breast cancer treatment through downregulating SIRT1/Akt pathway, leading to the valid management of breast cancer patients.