Abstract
Most advanced prostate cancers progress to castration resistant prostate cancer (CRPC) after a few years of androgen deprivation therapy and the prognosis of patients with CRPC is poor. Although docetaxel and cabazitaxel can prolong the survival of patients with CRPC, inevitable progression appears following those treatments. It is urgently required to identify better or alternative therapeutic strategies. The purpose of this study was to confirm the anti-cancer activity of zoledronic acid (Zol) and determine whether inhibition of geranylgeranylation in the mevalonate pathway could be a molecular target of prostate cancer treatment. We examined the growth inhibitory effect of Zol in prostate cancer cells (LNCaP, PC3, DU145) and investigated a role of geranylgeranylation in the anticancer activity of Zol. We, then, evaluated the growth inhibitory effect of geranylgeranyltransferase inhibitor (GGTI), and analyzed the synergy of GGTI and docetaxel by combination index and isobolographic analysis. Zol inhibited the growth of all prostate cancer cell lines tested in a dose-dependent manner through inhibition of geranylgeranylation. GGTI also inhibited the prostate cancer cell growth and the growth inhibitory effect was augmented by a combination with docetaxel. Synergism between GGTI and docetaxel was observed across a broad range of concentrations. In conclusion, our results demonstrated that GGTI can inhibit the growth of prostate cancer cells and has synergistic effect with docetaxel, suggesting its potential role in prostate cancer treatment.
Highlights
In about 80% of men with advanced metastatic prostate cancer, androgen deprivation therapy leads to improvement of symptoms and reduction of prostate specific antigen level
The cell growth assays showed that zoledronic acid (Zol) inhibited the growth of prostate cancer cells in a dose-dependent manner (Figure 1)
Bisphosphonates exert biological activities by inhibition of the synthesis of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, and inhibition of geranylgeranylation seems to be important for the activity of Zol [9, 10]
Summary
In about 80% of men with advanced metastatic prostate cancer, androgen deprivation therapy leads to improvement of symptoms and reduction of prostate specific antigen level. Prostate cancer cells progress to castrationresistant prostate cancer (CRPC) in the vast majority of patients. Docetaxel-based chemotherapy, for the first time, demonstrated a prolongation of survival in patients with CRPC [1, 2]. A combination of docetaxel and prednisone is current standard chemotherapy for CRPC. TROPIC, a phase III clinical trial, demonstrated survival advantage of cabazitaxel in patients who failed prior docetaxel therapy. The median survival in cabazitaxeltreatment group, was 15.1 months [3], and almost all will progress. It is still urgently required to identify better or alternative therapeutic strategies for improving treatment outcome
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