Abstract 5452: Discovery of a novel seleno-leonurine analog as a potential therapeutic for ovarian cancer

Abstract

Leonurine is an active alkaloid that is extracted from Traditional Chinese Medicine Herba leonuri. It has been reported to be beneficial for cardiovascular diseases, including atherosclerosis, acute and chronic myocardial infarction (MI), and ischemic stroke. Mao et al. illustrated that leonurine could up-regulate the expression of phosphorylated p38 and down-regulate phosphorylated Akt expression through inhibiting mitochondrial pathway, thus suppressing the proliferation and promoting lung cancer cell apoptosis. Accumulating evidence suggest that the extract of Leonurus sibiricus transgenic roots could induce apoptosis in different grades of human glioma cells and significantly promotes cisplatin sensitivity in cervical cancer cells via repressing cell proliferation, improving intrinsic cell apoptosis and inhibiting the expression of P-Gp and MRP1 protein, which has potential therapeutic value in cervical cancer treatment. In the present study, we designed and synthesized several selenium analogs of leonurine and their cytotoxicity were assessed using four different ovarian cancer cell lines viz. OVCAR-3, OVCAR-10, ES2, and drug resistant HeyA8 cells. Compared to the control and leonurine group, compound 834 inhibited the ovarian cancer cell viability in dose- and time-dependent manner. The IC50 values of compound 834 was 4.6 µM, 3.8 µM, 6.2 µM, and 5.7 µM for OVCAR-3, HeyA8, OVCAR-10, and ES2 cells, respectively, while for leonurine the IC50 value was >500 µM for 48 h treatment. To further acquaint the effect of 48 h treatment on cell proliferation, we performed trypan blue cell viability assay, trypan blue dye exclusion assay, Annexin V/7-AAD, Caspase 3/7 apoptosis assays and Western blotting of apoptotic proteins involved in apoptosis. Compound 834 significantly induced apoptosis in OVCAR-3 and HeyA8 cells in dose dependent manner. Upregulation of several apoptotic proteins, as evident by Western blot, suggested that 834 causes induction of apoptotic pathways efficiently. Further, the cell cycle analysis showed a significant arrest of OVCAR-3 and HeyA8 cells in the S-phase, which was further confirmed by the analysis of cyclin A2, cyclin-E1, p21 and p27 proteins expression. Conclusively, our research revealed that leonurine analog 834 significantly induces apoptosis in ovarian cancer cells via repressing cell proliferation, improving intrinsic cell apoptosis and inhibiting the expression of several signaling proteins, which has potential therapeutic value in ovarian cancer treatment.

Citation Format: Asif Raza, Jacek Krzeminski, Shantu Amin, Arun Sharma. Discovery of a novel seleno-leonurine analog as a potential therapeutic for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5452.