THU542 Inhibiting Oxidosqualene Cyclase Suppresses Cancer Stem-like Cells And Growth Of Epithelial Ovarian Cancer Cells In Vitro And In Vivo

Abstract

Abstract Disclosure: Y. Liang: None. K.P. Nephew: None. S.M. Hyder: None. Epithelial ovarian cancer (EOC) is an aggressive and deadly disease and despite concerted efforts to develop new strategies for preventing and treating the disease, almost 25,000 new cases are reported each year in the United States. Unfortunately, patients with ovarian cancer have poor prognosis due to the emergence of drug resistant cells and subsequent metastasis and have the highest mortality rate of all known gynecological malignancies. Standard treatments include systemic high-dose toxic chemotherapeutic drugs, but drug-resistance almost always occurs. Consequently, novel and more effective non-toxic therapies for ovarian cancer are urgently needed. The biosynthetic pathway leading to cholesterol production is an attractive therapeutic target since cholesterol is an essential structural and functional component of cell membranes and is necessary for tumor growth. Treatment with statins, a class of cholesterol biosynthesis inhibitors that target HMGCoA-reductase, is associated with certain undesirable side effects; consequently, alternative approaches to inhibit cholesterol biosynthesis are being considered. Epithelial ovarian cancer cells express enzymes in the cholesterol biosynthetic pathway. With this is mind we inhibited a key enzyme in the pathway, oxidosqualene cyclase (OSC), with a view to disrupting cholesterol biosynthesis and disrupting the progression of ovarian cancer. Potent small molecule inhibitors of OSC have been identified, and RO 48-8071 (4′-[6-(allylmethylamino)hexyloxy]-4-bromo-2′-fluorobenzophenone fumarate) (RO), has emerged as a useful chemotherapeutic agent for treating breast and prostate cancer. Since OSC acts downstream of HMG-CoA reductase during cholesterol biosynthesis, its inhibition is not likely to be associated with the adverse effects caused by statins. We found in short-term assays (24-48 h) that pharmacological doses very effectively reduced the viability of ovarian tumor cells (SK-OV-3 and OVCAR-3), determined by Sulforhodamine B colorimetric assay. In long-term assays (7 days), nM concentrations of the drug were also effective. Importantly, RO (20-40 mg/kg/day; ip) significantly suppressed tumor xenografts derived from ovarian cancer cells (SK-OV-3; 336 + 60 mm3 vs 171 + 20 mm3) with no toxicity to experimental animals (27 treatments once tumors reached 100 mm3). Mechanistically, RO induced apoptosis in EOC, and suppressed ALDH activity, indicating that the inhibitor suppresses stem cell-like activity of EOC. Our study is the first to demonstrate disruption of cholesterol biosynthesis in human ovarian cancer cells as a novel and potent means by which to suppress their growth. Further studies will determine whether combining RO with chemotherapeutic drugs is an even more effective therapeutic approach to EOC, and examine the effects of RO on combating the development of drug-resistant ovarian cancer. Presentation: Thursday, June 15, 2023