Tanshinone IIA is synergistic with the PARP inhibitor olaparib in inducing BRCAs-proficient and -deficient triple-negative breast cancer cell apoptosis.

Poly ADP-ribose Polymerase (PARP) inhibitor-based targeted therapy benefits the triple-negative breast cancer (TNBC) patients with Breast cancer susceptibility genes (BRCAs) mutation. However, only about 50% BRCA-mutated TNBC patients respond to PARP inhibitor treatment and 80% TNBC patients are BRCA proficient, which limit clinical application of PARP inhibitor for TNBC treatment. Ataxia-telangiectasia mutated (ATM) is a DNA double-strand break (DSB) sensor to detect and facilitate DSB repair. ATM deficiency sensitizes cancer cells to PARP inhibitor. Currently, none of ATM inhibitor is approved for clinical use largely due to toxicity. Tanshinone IIA (Tan IIA) is a natural compound derived from Salvia miltiorrhiza and has been approved for clinical application for cardiovascular diseases treatment in China. This study aims to evaluate whether Tan IIA could sensitize both BRCAs-proficient and -deficient TNBC cells to PARP inhibitor (olaparib) and explore the underlying molecular mechanisms. We report that Tan IIA synergistically enhances the cytotoxic effects of olaparib in both BRCA-proficient and -deficient TNBC cells. Tan IIA increases DSBs in TNBC cells and subsequently triggers apoptosis by destabilizing ATM. The results suggest that Tan IIA is a potential combinatory drug to enhance PARP inhibitor efficacy in TNBC treatment.