Targeting the ataxia telangiectasia mutated pathway for effective therapy against hirsutine-resistant breast cancer cells

Abstract

The present authors have recently demonstrated that hirsutine, one of the major alkaloids in Uncaria species, promotes cell apoptosis by inducing DNA damage and suppresses metastasis of breast cancer cells. Despite its potent anti-cancer activity, certain types of human breast cancer cells exhibit resistance to hirsutine. To maximize the clinical utility of hirsutine therapy against breast cancer, it is critical to explore the underlying mechanism that protects hirsutine-resistant breast cancer cell lines. To identify potential targets for overcoming hirsutine-resistance, the present study investigated a library of kinase inhibitors in combination with hirsutine treatment in the hirsutine-resistant human breast carcinoma MCF-7 cell line. Amongst the 96 compounds tested, inhibitors of the ataxia telangiectasia mutated (ATM) pathway sensitized MCF-7 cells to hirsutine-induced cell death along with a sustained DNA damage response. This sensitization of MCF-7 cells to the hirsutine-induced DNA damage response by interfering with the ATM pathway did not require p53. Instead, radical oxygen species generation was significantly increased in hirsute and ATM inhibitor-treated MCF-7 cells. In conclusion, the present findings suggest the importance of the ATM pathway for optimizing the anti-cancer effect of hirsutine in breast cancer cells.