Abstract C091: Liquiritigenin, an estrogen receptor beta agonist, enhances cholesterol biosynthesis inhibitor RO 48-8071-induced growth inhibition of ovarian cancer cells

Abstract

Abstract Almost 25,000 new cases of epithelial ovarian cancer (EOC) are reported each year in the United States. Cancers of the ovary have poor prognosis due to late detection, drug resistance and metastasis, and have the highest mortality rate of all the known gynecological malignancies. Despite concerted efforts to develop new strategies for preventing and treating ovarian cancer, novel and more effective non-toxic therapies are urgently needed. Recent observations from our laboratory show that RO 48-8071 ([4’-[6-(Allylmethylamino)hexyloxy]-4-bromo-2’-fluorobenzophenone fumarate] [RO], a small-molecule inhibitor of the key cholesterol biosynthesis enzyme 2, 3-oxidosqualene cyclase (OSC), inhibits breast and prostate cancer cells in vitro and in vivo. Further studies showed that RO also suppresses ovarian cancer cells, both in vitro and in vivo (Cholesterol Biosynthesis Inhibitor RO 48-8071 Suppresses Growth of Epithelial Ovarian Cancer Cells in Vitro and In Vivo. Journal of Cancer Science and Clinical Therapeutics 7 (2023): 01-08.). In short term assays (24h), pharmacological doses of RO (uM) suppressed ovarian cancer cell viability. In long-term assays (7 days) the same effects were observed in response to RO in the nM range. Interestingly, RO induced the tumor-suppressor protein estrogen receptor-beta (ER-beta) in both breast- and prostate-cancer cells and inhibited growth of xenografts of both types of tumor cells. We tested whether RO treatment also enhanced tumor-suppressor ER-beta expression in ovarian cancer cells and whether ER-beta agonists might enhance the effects of RO. Using Western blot analysis, we found that RO indeed induced ERb expression in OVCAR-3 ovarian-cancer cells, and that treatment of two ovarian-cancer cell lines (OVCAR-3 and SK-OV-3) with liquiritigenin (LQ), a naturally occurring ER-beta agonist derived from plants, enhanced RO mediated reduction in vitro. Treatment with RO (5-10 uM), LQ (100-300 uM), or RO + LQ (multiple combinations of doses) reduced cell viability; RO + LQ combination treatment synergistically reduced cell viability. We predict that our observed in vitro effects will be translatable to in vivo models, given that we have already demonstrated that RO alone quite effectively inhibits the in vivo growth of EOC xenografts. Since treatment of ovarian cancer with existing anti-cancer drugs is accompanied by extreme side effects and drug resistance, we propose that low-dose combinations of RO and LQ should be further explored as a potential new therapy for combatting this disease. Our findings contribute to ongoing efforts to identify novel, effective treatments for primary and metastatic ovarian cancer that employ new non-toxic drugs. Further in vivo studies examining the effects of RO + LQ combination treatment on EOC are warranted as a means of exploring a potential new therapeutic approach to combat ovarian cancers with minimal toxicity. Citation Format: Yayun Liang, Salman Hyder. Liquiritigenin, an estrogen receptor beta agonist, enhances cholesterol biosynthesis inhibitor RO 48-8071-induced growth inhibition of ovarian cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C091.