Pitavastatin and Ivermectin Enhance the Efficacy of Paclitaxel in Chemoresistant High-Grade Serous Carcinoma

SIMPLE SUMMARY: The main challenge in high-grade serous carcinoma management is to unveil therapeutic approaches to overcome chemoresistance. Drug combinations and repurposing of non-oncological agents are attractive strategies that allow for higher efficacy, decreased toxicity, and the overcoming of chemoresistance. Several non-oncological drugs display an effective anti-cancer activity and have been studied to be repurposed in multi-drug resistant neoplasms. The purpose of our study was to explore whether combining Paclitaxel with repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) led to a therapeutic benefit. Our results showed that the combination of Paclitaxel with Pitavastatin or Ivermectin demonstrates the highest cytotoxic effect and the strongest synergism among all combinations for two chemoresistant cell lines. Thus, the combination of these repurposed drugs with Paclitaxel could be a particularly valuable strategy to treat ovarian cancer patients with intrinsic or acquired chemoresistance. ABSTRACT: Chemotherapy is a hallmark in high-grade serous carcinoma management; however, chemoresistance and side effects lead to therapeutic interruption. Combining repurposed drugs with chemotherapy has the potential to improve antineoplastic efficacy, since drugs can have independent mechanisms of action and suppress different pathways simultaneously. This study aimed to explore whether the combination of Paclitaxel with repurposed drugs led to a therapeutic benefit. Thus, we evaluated the cytotoxic effects of Paclitaxel alone and in combination with several repurposed drugs (Pitavastatin, Metformin, Ivermectin, Itraconazole and Alendronate) in two tumor chemoresistant (OVCAR8 and OVCAR8 PTX R P) and a non-tumoral (HOSE6.3) cell lines. Cellular viability was assessed using Presto Blue assay, and the synergistic interactions were evaluated using Chou–Talalay, Bliss Independence and Highest Single Agent reference models. The combination of Paclitaxel with Pitavastatin or Ivermectin showed the highest cytotoxic effect and the strongest synergism among all combinations for both chemoresistant cell lines, resulting in a chemotherapeutic effect superior to both drugs alone. Almost all the repurposed drugs in combination with Paclitaxel presented a safe pharmacological profile in non-tumoral cells. Overall, we suggest that Pitavastatin and Ivermectin could act synergistically in combination with Paclitaxel, being promising two-drug combinations for high-grade serous carcinoma management.