Introduction While recent advances in ovarian cancer therapy have improved patient’s lives, current therapies are highly toxic. We developed sulfur heteroarotinoid A2 (SHetA2), a non-toxic drug currently in Phase 1 trial. SHetA2 causes cyclin D1 degradation and cyclin-dependent kinases 4 and 6 (CDK4/6) from protection by heat shock cognate 70 protein, causing G1 cell cycle arrest. Abemaciclib is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor used to treat breast cancer. We hypothesized that combination of SHetA2 and abemaciclib synergistically reduces cell lines- and ascites- derived spheroids viability as both drugs target different proteins in the cyclinD1/CDK4/6 complex critical for G1 to S progression.

Methods Ovarian cancer spheroids were developed from ES2 and OVCAR8 ovarian cancer cells lines using ultra-low attachment plates. Ascites-derived spheroids were collected from ovarian cancer patients who were undergoing paracentesis for ascites removal after receiving their informed consent. The half maximal inhibitory concentration (IC₅₀) for spheroids or ascites-derived spheroids was determined using CellTiter-Glo® 3D Cell Viability Assay. GraphPad Prism was used to calculate IC₅₀ for single drugs, while combination indexes were determined using CompuSyn.

Results Ovarian cancer spheroids IC₅₀ values ranged between 3–10 µM and 10–15 µM for SHetA2 and abemaciclib, respectively. There were synergistic effects when abemaciclib and SHetA2 were combined at doses above IC₅₀ of both drugs for cell line and ascites-derived spheroids.

Conclusion/Implications Findings from this study support the combination of SHetA2 and abemaciclib as a novel, less toxic therapy for ovarian cancer. Animal models will be carried out to validate these findings.