MalforminA1 reverts cisplatin resistance by modulating oncogenic signaling pathways in ovarian cancer

Ovarian cancer is a highly lethal gynecological malignancy, largely due to its late-stage diagnosis, frequent recurrence, and the development of chemoresistance. Standard treatment typically involves surgical debulking followed by chemotherapy, most commonly with platinum-based agents such as cisplatin. Unfortunately, many patients eventually develop resistance to these therapies, reducing treatment effectiveness and contributing to poor overall survival. These clinical challenges underscore the urgent need for novel therapeutic strategies that can overcome or prevent chemoresistance. Marine-derived compounds have recently emerged as a valuable source of potential anticancer agents, with several demonstrating potent biological activity. In our previous work, we identified multiple marine-derived molecules with promising anti-cancer properties, including Malformin A1 (MA1). MA1, a cyclic pentapeptide isolated from the marine fungus Aspergillus niger , exhibits cytotoxic activity against both cisplatin-sensitive (A2780S) and cisplatin-resistant (A2780CP) ovarian cancer cell lines. Building on these findings, the present study sought to elucidate the molecular pathways through which MA1 may reverse cisplatin resistance in ovarian cancer. In this study, we assessed the molecular pathways through which MA1 modulates cisplatin resistance in A2780CP cells, using the cisplatin-sensitive A2780S cell line as a reference. The expression of key cancer-related proteins, including ERK1/2 and NF-κbeta, was analyzed by Western blot to evaluate the modulatory effects of MA1 on these signaling pathways. MA1 treatment resulted in a significant reduction of total MEK1/2, ERK1/2, and NF-κbeta protein levels in A2780S cells, whereas in A2780CP cells, only NF-κbeta expression was increased. Furthermore, phosphorylated ERK1/2 and NF-κbeta levels were elevated, particularly in A2780CP cells, indicating activation of ERK1/2 and NF-κbeta pathways, which play central roles in regulating cell survival and apoptosis. The cytotoxic effects of MA1 were more pronounced in cisplatin-resistant A2780CP cells, supporting the compound's potential role in reversing cisplatin resistance. Activation of these signaling pathways following MA1 treatment may resensitize resistant cells to apoptosis or other cytotoxic mechanisms, thereby contributing to the overcoming of chemoresistance.In conclusion, our findings demonstrate that MA1 can reverse cisplatin resistance through the modulation of key oncogenic signaling pathways, highlighting its promise as a therapeutic candidate to improve treatment outcomes in ovarian cancer.