Antineoplastic Drug Synergy of Artesunate with Navitoclax in Models of High-Grade Serous Ovarian Cancer

Simple Summary Modern ovarian cancer treatment has not substantially improved outcomes, and superior therapeutic strategies are needed. The aim of this study was to evaluate the efficacy of artesunate and navitoclax drug combination in ovarian cancer. We determined the combination of these two drugs was extraordinarily effective in multiple models of ovarian cancer, in vitro, inhibiting cancer cell proliferation more than expected based on single-agent activities. Unfortunately, we were unable to validate these findings using a mouse model of metastatic ovarian cancer. These data provide valuable information regarding the potential utility and challenges associated with the artesunate/navitoclax drug combination for ovarian cancer therapy.Abstract Artesunate belongs to a class of medications derived from the sweet wormwood plant (Artemisia annua) known as artemisinins. Artesunate has traditionally been used as a frontline treatment for severe malaria but has also demonstrated antineoplastic activity against various malignancies, including ovarian cancer. Data suggest that artesunate exacerbates cellular oxidative stress, triggering apoptosis. In the current study, we investigated the ability of navitoclax, an inhibitor of the antiapoptotic Bcl-2 protein family, to enhance artesunate efficacy in ovarian cancer cells. Artesunate and navitoclax both demonstrated antiproliferative effects on 2D and 3D ovarian cancer cell models as single agents. Upon combination of navitoclax with artesunate, antineoplastic drug synergy was also observed in each of the 2D cell lines and ovarian tumor organoid models tested. Further investigation of this drug combination using intraperitoneal CAOV3 xenograft models in BALB/scid mice showed that the artesunate/navitoclax doublet was superior to single-agent artesunate and vehicle control treatment. However, it did not outperform single-agent navitoclax. With optimization, this drug combination could provide a new therapeutic option for ovarian cancer and warrants further preclinical investigation.