Synergistic Antitumor Activity of DA-10 and Niraparib by Overcoming Platinum Resistance in Ovarian Cancer

INTRODUCTION: While PARP inhibitors have shown effectiveness in treating platinumsensitive ovarian cancer, their therapeutic efficacy is notably reduced in cases of platinumresistant disease. This limitation highlights the urgent need for developing combination strategies that can enhance the response to PARP inhibitors in platinum-resistant ovarian cancer. METHODS: This study explores the therapeutic potential and mechanisms of combining dolastatin 10 (DA-10) with niraparib in platinum-resistant models, highlighting their cytotoxic synergy and promising patent prospects. In vitro assays, including cell proliferation, colony formation, apoptosis, and DNA damage quantification, were conducted using cisplatin-resistant A2780 and SKOV3 cell lines. The in vivo efficacy and synergy were evaluated in xenograft tumor models. Mechanistic studies focused on DNA damage accumulation, PARP activity, and microtubule stability. RESULTS: The co-treatment of DA-10 with niraparib significantly inhibited cell proliferation and colony formation, while substantially increasing DNA damage levels and apoptosis in platinumresistant A2780 and SKOV3 cell lines. The synergistic inhibition of tumor growth was further validated in vivo through xenograft models. Mechanistically, the combination treatment synergistically suppressed PARP activity and destabilized microtubules. DISCUSSION: These findings suggest that concurrent disruption of DNA repair and microtubule stability contributes to the observed synergy and may help overcome mechanisms underlying platinum resistance. Further studies in broader preclinical models will be needed to refine the mechanistic basis and assess translational potential. CONCLUSION: The synergistic interaction between DA-10 and niraparib demonstrates significant potential to overcome platinum resistance in ovarian cancer. This novel combinatorial strategy represents a patentable therapeutic approach for platinum-resistant ovarian cancer, offering insights for future translational clinical trials assessing the efficacy of DA-10 in combination with niraparib.