Synergistic Effect of Geranylgeranyltransferase Inhibitor, GGTI, and Docetaxel on the Growth of Prostate Cancer Cells

摘要

Most advanced prostate cancers progress to castration resistantprostate cancer (CRPC) after a few years of androgen deprivationtherapy and the prognosis of patients with CRPC is poor. Althoughdocetaxel and cabazitaxel can prolong the survival of patientswith CRPC, inevitable progression appears following thosetreatments. It is urgently required to identify better oralternative therapeutic strategies. The purpose of this study wasto confirm the anti-cancer activity of zoledronic acid (Zol) anddetermine whether inhibition of geranylgeranylation in themevalonate pathway could be a molecular target of prostate cancertreatment. We examined the growth inhibitory effect of Zol inprostate cancer cells (LNCaP, PC3, DU145) and investigated a roleof geranylgeranylation in the anticancer activity of Zol. We,then, evaluated the growth inhibitory effect ofgeranylgeranyltransferase inhibitor (GGTI), and analyzed thesynergy of GGTI and docetaxel by combination index andisobolographic analysis. Zol inhibited the growth of all prostatecancer cell lines tested in a dose-dependent manner throughinhibition of geranylgeranylation. GGTI also inhibited theprostate cancer cell growth and the growth inhibitory effect wasaugmented by a combination with docetaxel. Synergism between GGTIand docetaxel was observed across a broad range of concentrations. In conclusion, our results demonstrated that GGTI can inhibit thegrowth of prostate cancer cells and has synergistic effect withdocetaxel, suggesting its potential role in prostate cancertreatment.