Abstract 610: Manzamine and mitragynine: investigation of beta carboline compounds from marine sponges and kratom leaves as ovarian cancer therapeutics

Epithelial ovarian cancer (EOC) is the leading cause of death among gynecologic cancers. Five-year survival rates hover around 35%, largely due to widely metastatic and drug-resistant recurrent disease. Prior studies in our laboratory and others have shown that tumor progression, as evidenced by epithelial to mesenchymal transition (EMT) and metastasis, can have a significant impact on the response of cancer cells to treatment. Tumor heterogeneity is a substantial barrier to effective therapy. For instance, stem-like cells can withstand treatment that eliminates faster-growing cells and have the potential to give rise to recurrence. Thus, novel therapies or drug combinations that can eliminate all subpopulations within a tumor are needed. Natural products have a long history in cancer treatment. Prior studies in the natural products space on anti-EMT drugs focused on the beta carboline molecule harmine and its derivatives. While these compounds have shown efficacy, translation of these compounds to the clinic is complicated by their hallucinogenic properties. Therefore, we sought alternatives with similar beta carboline moieties. In the present study, we investigated alkaloids from marine sponges (Halicloa spp.) and the kratom plant (Mitragyna speciosa) as potential therapeutics for EOC. We tested the kratom compound mitragynine, the marine compound manzamine A, and several of their derivatives and analogues, in multiple EOC cell lines. We found that mitragynine killed EOC cells with an IC50 of ∼20 µM. The marine alkaloid manzamine A killed EOC cells with IC50 values in the low micromolar range. Each of these outperformed their respective analogues in cell survival assays. Importantly, both pre- and post-EMT cells, and models of primary and recurrent disease, all responded to manzamine treatment. Our findings also suggest an additive effect when manzamine therapy is combined with conventional chemotherapy. Additional work will be needed to fully elucidate the full mechanism of action of these compounds and whether inclusion of these alkaloids in treatment regimens will be effective in combating drug resistance. However, our results suggest that there is a place for these compounds in our arsenal for the deadliest gynecologic cancers. Citation Format: Ashley Gabriel, Haifa Sahouri, Helen Fischer, Kimberly A. Gonzalez, Jihad Aburas, Cai M. Roberts. Manzamine and mitragynine: investigation of beta carboline compounds from marine sponges and kratom leaves as ovarian cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 610.