Liarozole potentiates retinoic acid effects on human prostate carcinoma cells

Metastatic prostate adenocarcinoma is a leading cause of death in men. Retinoic acid (RA) is an effective chemopreventive and differentiation inducing agent, acting through its nuclear receptors (RARα, β, y). A major problem in RA differentiation therapy is that RA induces its own catabolism by cytochrome P450s, so that blood RA levels drop by 10-20 fold after one week of therapy. Liarozole (LZ), a novel imidazole derivative, inhibits the cytochrome P450s involved in RA catabolism and may increase intracellular RA. available for gene activation. We tested this hypothesis in LNCaP human prostate adenocarcinoma cells and in Dunning 145 (DU 145) cells, derived from brain metastasis of human prostate carcinoma 1 ) by measuring growth inhibition by RA alone and in combination with LZ, and 2) by studying the induction of transglutaminase type II (TGase II) activity, a RA taiget gene Inhibition of carcinoma cell growlh by these agents was evident at day 2 of culture and reached a maximum at day 7 (42% for RA, and 71% for the combination of RA and LZ), suggesting a synergistic effect. RA induced TGase II activity by 33%, and the combination of RA and LZ by 118% Since TGase is an indicator of apoptotis, our data suggest that RA, as well as LZ, activate cell death in these prostate carcinoma cells. The use of I.Z may create sufficiently elevated concentrations of R A in target cells to induce their irreversible demise via programmed cell death.