Combinative Treatment of the PARP Inhibitor Olaparib and Antimetastasis Ruthenium(II)-Arene Compound RAPTA-T for...

To date, breast cancer remains one of the leading causes of death among women worldwide. Although various treatments are used in clinical settings, the efficacy and safety of such treatments are limited by tumor biology factors and patient preferences. Previous studies have shown that triple-negative BRCA1-deficient breast cancer is susceptible to DNA-damaging agents, including platinum-based drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, alone or in combination. To address whether the combinative treatment of these DNA-damaging agents can be extended to the triple-negative BRCA1-proficient breast cancer population, we investigated the anticancer activity of the well-known FDA-approved PARP inhibitor olaparib in combination with the antimetastatic ruthenium(II)-arene PTA compound RAPTA-T for triple-negative BRCA1-competent breast cancer cells (MDA-MB-468 and MDA-MB-231), with consideration of sporadic breast cancer MCF-7 cells. RAPTA-T, olaparib, and the combined agents exhibited a dose-dependent inhibition of breast cancer cell growth in selected breast cancer cells. The combination compound inhibited colony formation most effectively in MDA-MB-468 cells. Additionally, the scratch-wound assay showed that MDA-MB-468 cells migrated more slowly than MCF-7 and MDA-MB-231 cells. The results indicated that the olaparib and RAPTA-T combination can reduce or inhibit the survival, invasion, and metastasis of breast cancer cells. Moreover, the combined agents promoted apoptotic cell death, with a higher percentage of apoptosis observed in MDA-MB-468 cells than in MDA-MB-231 and MCF-7 cells. Olaparib and RAPTA-T also interfered with cell cycle progression, with the greatest inhibition observed in the S and G2/M phases of MCF-7 cells (1.6- and 3.4-fold), followed by MDA-MB-468 cells (1.6- and 1.8-fold) and MDA-MB-231 cells (1.5- and 1.4-fold). Interestingly, MDA-MB-468 cells presented the highest degree of inhibition for BRCA1 replication and BRCA1 expression. The p53, PARP, and Chk1 proteins were more strongly upregulated in MDA-MB-231 cells than in Ru-untreated control cells. Moreover, the expression levels of protein biomarkers associated with the epithelial-to-mesenchymal transition (EMT), including E-cadherin and SLUG, were remarkably reduced in all tested breast cancer cells. Together, our results show the feasibility of extending the application of PARP inhibitors beyond breast cancer with BRCA1 mutations and optimizing the combinative treatment of PARP inhibitors with antimetastasis ruthenium-based chemotherapy as new therapeutic approaches for TNBC harboring wild-type BRCA1.