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