%0 Journal Article
%T Synergistic Effect of Geranylgeranyltransferase Inhibitor, GGTI, and Docetaxel on the Growth of Prostate Cancer Cells
%A Bin Han
%A Naohiro Fujimoto
%A Mizuki Kobayashi
%A Tetsuro Matsumoto
%J Prostate Cancer
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/989214
%X 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. 1. Introduction 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. However, prostate cancer cells progress to castration-resistant 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]. Therefore, a combination of docetaxel and prednisone is current standard chemotherapy for CRPC. However, inevitable progression occurs after docetaxel treatment. TROPIC, a phase III clinical trial, demonstrated survival advantage of cabazitaxel in patients who failed prior docetaxel therapy. The median survival in cabazitaxel- treatment group, however, was 15.1 months [3], and almost all will progress. Thus, it is still urgently required to identify better or alternative therapeutic strategies for improving treatment outcome. Bisphosphonates reduce skeletal complications in advanced malignant
%U http://www.hindawi.com/journals/pc/2012/989214/