5,6 dihydro-5 '-azacytidine (DHAC) restores androgen responsiveness in androgen-insensitive prostate cancer cells

Introduction: The androgen resistance of some prostate cancer patients may be due to transcriptional inactivation of the androgen receptor (AR) gene c atalyzed by cytosine DNA methyltransferase. Materials and Methods: To deter mine if an inhibitor of cytosine DNA methyltransferase, 5,6-dihydro-5'-azac ytidine (DHAC), can restore the androgen sensitivity in androgen-insensitiv e human prostate carcinoma cell lines in vitro, we cultured androgen-insens itive (PC3, DU-145, and TSUPrl) and androgen-responsive (LNCaP) cells with subcytotoxic concentrations (less than or equal to IC50) of DHAC for 14 day s followed by exposure to dihydrotestosterone (DHT) or to hydroxyflutamide for 7 days. Results and Conclusions: Only DHAC-treated DU-145 cells showed growth stimulation by 10(-11) to 10(-9) M DHT and a partial inhibition by 1 0(-5) and 10(-6) M hydroxyflutamide. However, since DU-145 is the only cell line tested that is known to have a hypermethylated AR promoter, the obser ved effects may be due to a partial demethylation of the AR by DHAC. Our da ta provide an evidence that cytosine DNA methyltransferase inhibitors can r estore androgen responsiveness in androgen-refractory tumor cells, which ar e then sensitive to growth inhibition by antiandrogens.