LIGAND FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (TROGLITAZONE) HAS POTENT ANTITUMOR EFFECT AGAINST HUMAN PROSTATE-CANCER BOTH IN-VITRO AND IN-VIVO

Citation
T. Kubota et al., LIGAND FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (TROGLITAZONE) HAS POTENT ANTITUMOR EFFECT AGAINST HUMAN PROSTATE-CANCER BOTH IN-VITRO AND IN-VIVO, Cancer research, 58(15), 1998, pp. 3344-3352
Citations number
39
Categorie Soggetti
Oncology
Journal title
ISSN journal
00085472
Volume
58
Issue
15
Year of publication
1998
Pages
3344 - 3352
Database
ISI
SICI code
0008-5472(1998)58:15<3344:LFPPR(>2.0.ZU;2-C
Abstract
Troglitazorne, a thiazolidinedione derivative, is a widely used antidi abetic drug that binds and activates peroxisome proliferator-activated receptor gamma (PPAR gamma) and enhances insulin sensitivity. It indu ces differentiation of adipocytes, which highly express PPAR gamma We report that human prostate cancer cells expressed PPAR gamma at promin ent levels and normal prostate tissues had very low expression. Dose-r esponse clonogenic assays of the PC-3 prostate cancer cell line with t roglitazone showed an antiproliferative effect (ED50, 3 x 10(-7) M) an d other PPAR gamma ligands (BRL49653: ED50, 8 x 10(-8) M; 15-deoxy-Del ta(12,14)-prostaglandin J(2): ED50, 2 x 10(-6) M; ciglitizone: ED50, n ot reached; indomethacin: ED50, not reached) shelved similar effects. Combinations of traglitazone and a ligand specific for either retinoid X receptor or retinoic acid receptor did not show a synergistic effec t. Pulse-exposure to troglitazone (10(-5) M) for different durations s helved that 4 days of pulse-exposure to the agent irreversibly inhibit ed 50% clonal growth of PC-3 cells. Interestingly, PC-3 cells cultured with troglitazone (10(-5) M) showed dramatic morphological changes bo th by light and electron microscopy, suggesting that the cells became Less malignant. Nevertheless, troglitazone did not affect either the c ell cycle or several markers of differentiation. LNCaP cells constitut ively produced prostate-specific antigen, and levels were markedly enh anced by all-trans-retinoic acid. Troglitazone (10(-5) M, 4 days) decr eased by 50% the levels of prostate-specific antigen produced by these cells. In vivo treatment of PC-3 tumors growing in male BNX triple im munodeficient mice with oral troglitazone (500 mg/kg/day) produced sig nificant inhibition of tumor growth (P = 0.01). The only objective sid e effect of troglitazone in mice was the elevation of serum transamina ses. Short-term culture of four surgically obtained human prostate can cer tumors with troglitazone (10(-5) M, 4 days) produced marked and se lective necrosis of the cancer cells (about 60%) but not the adjacent normal prostate cells. Taken together, these results suggest that trog litazone may be a useful therapeutic agent for the treatment of prosta te cancer, especially in the setting of low disease burden.