Synergistic antitumor effects and mechanistic insight of hypericin-mediated photodynamic therapy combined with Olaparib in MCF-7 BRCA1 wild-type breast cancer cells.

Breast cancer remains a leading cause of cancer-related mortality in women worldwide. Hypericin (HYP) is a natural photosensitizer and hypericin-mediated photodynamic therapy (HYP-PDT) has shown promise in cancer treatment. PARP inhibitors like Olaparib are effective in BRCA1-mutant breast cancers but have limited efficacy in BRCA1 wild-type breast cancer. This study investigated the synergistic antitumor effects of HYP-PDT combined with Olaparib in BRCA1 wild-type breast cancer cells. MCF-7 cell line, a well-characterized and commonly utilized model for BRCA1 wild-type breast cancer was employed in this study. We evaluated the cellular responses to varying concentrations of HYP and Olaparib followed by PDT, through assessments of reactive oxygen species (ROS) production, DNA damage signaling pathways, apoptosis, cell cycle distribution, and migration capabilities. Results demonstrated that both HYP-PDT and Olaparib individually inhibited cell proliferation in a dose-dependent manner, with their combination synergistically enhancing antitumor efficacy. HYP-PDT induced intracellular ROS generation and DNA damage, which were further amplified by Olaparib. The combination treatment modulated the ATM/p53/RAD51 signaling pathway, leading to apoptosis and G2/M phase cell cycle arrest through the regulation of mitochondrial apoptosis-associated proteins and cell cycle checkpoint proteins. Furthermore, the combination treatment inhibited epithelial-to-mesenchymal transition (EMT), thereby reducing MCF-7 cell migratory capability. These findings highlight the potential of combining HYP-PDT with Olaparib as a promising strategy to overcome the limitations of monotherapies and provide a novel approach for treating BRCA1 wild-type breast cancer.