Effect and mechanism of STF-31 combined with cisplatin in overcoming platinum resistance in ovarian cancer.

e17594 Background: Platinum-based chemotherapy is currently the first-line treatment for ovarian cancer patients. However, tumor cells gradually develop resistance to these drugs after treatment. Therefore, there is an urgent need to identify drugs that can be used in combination with platinum-based agents to enhance their efficacy. To discover more targeted drugs that can synergistically kill tumor cells with platinum-based drugs, this study screened 359 small-molecule compounds in combination with cisplatin in platinum-resistant ovarian cancer cells. Methods: We conducted a screening of 359 small-molecule compounds in combination with cisplatin in platinum-resistant ovarian cancer cells. Among the compounds, we selected the GLUT1 inhibitor STF-31 for further investigation. Cell proliferation assays were performed to calculate synergy scores, and apoptosis and colony formation assays were used to evaluate the combined effects. Additionally, proteomic sequencing was employed to explore the underlying mechanisms of the synergistic effects. Results: The screening results showed that certain small-molecule compounds, including those previously reported to have synergistic effects with cisplatin (e.g., shikonin), exhibited favorable combined effects with cisplatin. Specifically, STF-31 significantly increased the sensitivity of tumor cells to cisplatin and carboplatin, demonstrating a synergistic effect. Mechanistically, the combination of STF-31 with cisplatin or carboplatin resulted in a higher apoptosis rate compared to the use of cisplatin, carboplatin, or STF-31 alone. Furthermore, proteomic sequencing revealed that STF-31 may influence the expression of MTA1, affecting ATP-dependent chromatin remodeling, which contributes to its synergistic effect with cisplatin. Conclusions: In conclusion, the findings of this study suggest that STF-31 has the potential to be used in combination with platinum-based drugs to effectively kill platinum-resistant ovarian cancer cells. By enhancing cisplatin- and carboplatin-induced apoptosis and modulating chromatin remodeling, STF-31 represents a promising candidate for overcoming platinum resistance in ovarian cancer treatment.