TAK1 inhibitor NG25 enhances doxorubicin-mediated apoptosis in breast cancer cells

Doxorubicin (Dox, Adriamycin) has been widely used in breast cancer treatment. But its severe cardio-toxic side effects limited the clinical use. Dox treatment can induce DNA damage and other accompanying effects in cancer cells, and subsequently activates nuclear factor kappa B (NF-kappa B) pathway which has a strong pro-survival role in different types of malignancy. We hypothesize that blocking NF-kappa B pathway may sensitize breast cancer cells to Dox chemotherapy. TGF beta-activated kinase-1 (TAK1) is a key intracellular molecule participating in genotoxic stresses-induced NF-kappa B activation. Targeting TAK1 as a strategy to enhance cancer treatment efficacy has been studied in several malignancies. We showed that NG25, a synthesized TAK1 inhibitor, greatly enhanced Dox treatment efficacy in a panel of breast cancer cell lines. In this pre-clinical study, we found that NG25 partially blocked Dox-induced p38 phosphorylation and I kappa B alpha degradation and enhanced Dox-induced cytotoxic effects and apoptosis in all breast cancer cell lines tested. Taken together, we provided clear evidence that NG25 sensitizes the breast cancer cells to Dox treatment in vitro. This combination may be an effective and feasible therapeutic option maximizing Dox efficacy and meanwhile minimizing Dox side effects in treating breast cancer.