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
References
[1]
D. P. Petrylak, C. M. Tangen, M. H. A. Hussain et al., “Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer,” New England Journal of Medicine, vol. 351, no. 15, pp. 1513–1520, 2004.
[2]
I. F. Tannock, R. De Wit, W. R. Berry et al., “Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer,” New England Journal of Medicine, vol. 351, no. 15, pp. 1502–1512, 2004.
[3]
J. S. De Bono, S. Oudard, M. Ozguroglu et al., “Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial,” The Lancet, vol. 376, no. 9747, pp. 1147–1154, 2010.
[4]
F. Saad, Y. M. Chen, D. M. Gleason, and J. Chin, “Continuing benefit of zoledronic acid in preventing skeletal complications in patients with bone metastases,” Clinical Genitourinary Cancer, vol. 5, no. 6, pp. 390–396, 2007.
M. Caraglia, D. Santini, M. Marra, B. Vincenzi, G. Tonini, and A. Budillon, “Emerging anti-cancer molecular mechanisms of aminobisphosphonates,” Endocrine-Related Cancer, vol. 13, no. 1, pp. 7–26, 2006.
[7]
A. J. Roelofs, K. Thompson, S. Gordon et al., “Molecular mechanisms of action of bisphosphonates: current status,” Clinical Cancer Research, vol. 12, no. 20, pp. 6222s–6230s, 2006.
[8]
T. C. Chou and P. Talalay, “Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors,” Advances in Enzyme Regulation, vol. 22, pp. 27–55, 1984.
[9]
M. Goffinet, M. Thoulouzan, A. Pradines et al., “Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells,” BMC Cancer, vol. 6, article 60, 2006.
[10]
J. P. Coxon, G. M. Oades, R. S. Kirby, and K. W. Colston, “Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation,” British Journal of Urology International, vol. 94, no. 1, pp. 164–170, 2004.
[11]
S. M. Sebti and A. D. Hamilton, “Anticancer activity of farnesyltransferase and geranylgeranyltransferase I inhibitors: prospects for drug development,” Expert Opinion on Investigational Drugs, vol. 6, no. 11, pp. 1711–1714, 1997.
[12]
A. Vogt, J. Sun, Y. Qian, A. D. Hamilton, and S. M. Sebti, “The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G/G and induces p21(WAF1/CIP1/SD11) in a p53-independent manner,” Journal of Biological Chemistry, vol. 272, no. 43, pp. 27224–27229, 1997.
[13]
J. H. Lin, “Bisphosphonates: a review of their pharmacokinetic properties,” Bone, vol. 18, no. 2, pp. 75–85, 1996.
[14]
J. Sun, Y. Qian, Z. Chen, J. Marfurt, A. D. Hamilton, and S. M. Sebti, “The geranylgeranyltransferase I inhibitor GGTI-298 induces hypophosphorylation of retinoblastoma and partner switching of cyclin- dependent kinase inhibitors: a potential mechanism for GGTI-298 antitumor activity,” Journal of Biological Chemistry, vol. 274, no. 11, pp. 6930–6934, 1999.
[15]
W. W. Stark Jr., M. A. Blaskovich, B. A. Johnson et al., “Inhibiting geranylgeranylation blocks growth and promotes apoptosis in pulmonary vascular smooth muscle cells,” American Journal of Physiology, vol. 275, no. 1, pp. L55–L63, 1998.
[16]
X. Li, L. Liu, J. C. Tupper et al., “Inhibition of protein geranylgeranylation and RhoA/RhoA kinase pathway induces apoptosis in human endothelial cells,” Journal of Biological Chemistry, vol. 277, no. 18, pp. 15309–15316, 2002.
[17]
M. A. Morgan, J. Wegner, E. Aydilek, A. Ganser, and C. W. M. Reuter, “Synergistic cytotoxic effects in myeloid leukemia cells upon cotreatment with farnesyltransferase and geranylgeranyl transferase-I inhibitors,” Leukemia, vol. 17, no. 8, pp. 1508–1520, 2003.
[18]
H. C. Dan, K. Jiang, D. Coppola et al., “Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis,” Oncogene, vol. 23, no. 3, pp. 706–715, 2004.
[19]
S. S. Virtanen, J. Sandholm, G. Yegutkin, H. K. V？？n？nen, and P. L. H？rk？nen, “Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells,” Cell Biology International, vol. 34, no. 8, pp. 815–826, 2010.
[20]
H. L. Neville-Webbe, A. Rostami-Hodjegan, C. A. Evans, R. E. Coleman, and I. Holen, “Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells,” International Journal of Cancer, vol. 113, no. 3, pp. 364–371, 2005.
[21]
S. P. Jagdev, R. E. Coleman, C. M. Shipman, H. A. Rostami, and P. I. Croucher, “The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel,” British Journal of Cancer, vol. 84, no. 8, pp. 1126–1134, 2001.
[22]
S. Matsumoto, S. Kimura, H. Segawa et al., “Efficacy of the third-generation bisphosphonate, zoledronic acid alone and combined with anti-cancer agents against small cell lung cancer cell lines,” Lung Cancer, vol. 47, no. 1, pp. 31–39, 2005.
[23]
K. Sato, T. Yuasa, M. Nogawa et al., “A third-generation bisphosphonate, minodronic acid (YM529), successfully prevented the growth of bladder cancer in vitro and in vivo,” British Journal of Cancer, vol. 95, no. 10, pp. 1354–1361, 2006.
[24]
M. N. A. Bijman, G. P. van Nieuw Amerongen, N. Laurens, V. W. M. van Hinsbergh, and E. Boven, “Microtubule-targeting agents inhibit angiogenesis at subtoxic concentrations, a process associated with inhibition of Rac1 and Cdc42 activity and changes in the endothelial cytoskeleton,” Molecular Cancer Therapeutics, vol. 5, no. 9, pp. 2348–2357, 2006.
