Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells

Abed, MN; Richardson, A; Abdullah, MI

Abstract

Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC50?=?0.6-14?µM), zoledronic acid (IC50?=?21-57?µM), risedronate (IC50?>?100?µM) or GGTI-2133 (IC50?>?25?µM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIß and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iß and GGT-IIß used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer.

Citation

Abed, M., Richardson, A., & Abdullah, M. (2017). Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells. Scientific reports, 8090 -?. https://doi.org/10.1038/s41598-017-08649-9

• Acceptance Date: Jul 11, 2017
• Publication Date: Aug 14, 2017
• Journal: Scientific Reports
• Print ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Pages: 8090 -?
• DOI: https://doi.org/10.1038/s41598-017-08649-9
• Publisher URL: http://dx.doi.org/10.1038/s41598-017-08649-9