Conclusion
Cholesterol biosynthesis inhibitor RO 48-8071 is thus a novel and potent inhibitor of human EOC, including EOC stem cells.
Methods
Cell viability assays were performed to determine effects of RO 48-8071 on growth of EOC cells. Aldehyde Dehydrogenase (ALDH) assay was conducted to determine the effects of drug on reducing stem cell like properties of EOC cells. Finally, xenograft studies were performed to assess the ability of RO 48-8071 to inhibit the growth of EOC cells in vivo.
Results
We found that short-term (24-48 h) administration of pharmacological doses of RO effectively reduced the viability of drug-resistant EOC cells (SK-OV-3 and OVCAR-3), as determined with sulforhodamine B colorimetric assays. In 7-day assays, nanomolar concentrations of RO effectively inhibited the growth of EOC cells. RO also suppressed ALDH activity, a marker of stem cells. Importantly, RO significantly suppressed growth of xenografts derived from EOC cells when given to mice intraperitoneally (20-40 mg kg-1 day-1) for 27 days once tumors reached 100 mm3 (controls: 336 + 60 mm3; treated: 171 + 20 mm3) with no toxicity to the experimental animals. Mechanistically, RO induced apoptosis in tumor cells in vivo as shown with immunohistochemistry.