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-IIβ and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iβ and GGT-IIβ 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.
Highlights
Ovarian cancer is the 5th leading cause of death in women with more than 14,000 deaths reported annually in United States[1]
The growth inhibitory activities of pitavastatin, zoledronic acid, risedronate and GGTI-2133 as single agents were first determined against a panel of ovarian cancer cell lines
Zoledronic acid had lower potency than pitavastatin and showed concentration-dependent growth inhibitory activity with IC50s ranging from 21–60 μM (Table 1)
Summary
Ovarian cancer is the 5th leading cause of death in women with more than 14,000 deaths reported annually in United States[1]. HMGCR activity may be deregulated in tumours, becoming resistant to negative feedback control by sterols and this may help provide an abundance of isoprenoids to promote growth of transformed cells[8] These isoprenoids are used to post-translationally modify several small GTPases superfamily proteins and support their membrane localization[9]. Geranylgeranyl transferase-β enzymes had been reported to be upregulated in several human tumors[11] This has raised interest in the mevalonate pathway as a potential target in oncology. Others, have shown that relatively high doses of statins are likely to be necessary to achieve an adequate plasma concentration of drug[20, 21] This raises concerns about the potential risk of myopathy, a side effect commonly associated with statins. Bisphosphonates can enhance the anticancer activity of several chemotherapeutic agents in vitro[27,28,29,30]
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