Ivosidenib enhances cisplatin sensitivity in ovarian cancer by reducing cancer cell stemness.

Abstract

Aim: Cancer stem cells (CSCs) are pivotal in mediating platinum resistance in ovarian cancer. This study aimed to screen compounds sensitizing CSCs to cisplatin by using a small molecule inhibitor library. Methods: A library of 105 common drugs was screened in ovarian CSC model SK-3rd and ovarian cancer platinum-resistant cell model SKDDP to identify those that could enhance sensitivity to cisplatin by MTT assay. The antitumor effect was assessed in ovarian cancer cells using the MTT assay, colony formation assay, and apoptosis assay. The impact on cancer cell stemness was evaluated using qPCR and Sphere-forming assays. Finally, the effect of the combination regimen was evaluated in patient-derived organoids (PDOs) under different treatments by the CellTiter-Glo Luminescence Assay. Results: The results of the initial screening on SK-3rd identified five candidate compounds. Rescreening on SKDDP showed that Ivosidenib was the most effective in sensitizing cisplatin. MTT, colony formation, and apoptosis assays demonstrated that Ivosidenib enhanced the sensitivity to cisplatin, inhibited proliferation, and induced apoptosis in ovarian cancer cells, including SK-3rd and SKDDP. Furthermore, Ivosidenib lowered stemness marker expression and countered CSC enrichment caused by platinum-based chemotherapy in ovarian cancer cells. Finally, the synergistic effect of this combination was also confirmed in three ovarian cancer PDOs. Conclusion: Ivosidenib may increase cisplatin sensitivity in ovarian cancer cells by decreasing their stemness, providing a potential therapeutic method for ovarian cancer patients.