5,6 Dihydro-5'-azacytidine (DHAC) restores androgen responsiveness in androgen-insensitive prostate cancer cells
Izbicka, E.; MacDonald, J.R.; Davidson, K.; Lawrence, R.A.; Gomez, L.; Von Hoff, D.D.
Anticancer Research 19(2a): 1285-1291
1999
ISSN/ISBN: 0250-7005 PMID: 10368689 Document Number: 500301
Introduction: The androgen resistance of some prostate cancer patients may be due to transcriptional inactivation of the androgen receptor (AR) gene catalyzed by cytosine DNA methyltransferase. Materials and Methods: To determine if an inhibitor of cytosine DNA methyltransferase, 5,6-dihydro-5'-azacytidine (DHAC), can restore the androgen sensitivity in androgen-insensitive human prostate carcinoma cell lines in vitro, we cultured androgen-insensitive (PC3, DU-145, and TSUPrl) and androgen-responsive (LNCaP) cells with subcytotoxic concentrations (ltoreqIC50) of DHAC for 14 days 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 10-5 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 observed effects may be due to a partial demethylation of the AR by DHAC. Our data provide an evidence that cytosine DNA methyltransferase inhibitors can restore androgen responsiveness in androgen-refractory tumor cells, which are then sensitive to growth inhibition by antiandrogens.