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

Anticancer Res. Mar-Apr 1999;19(2A):1285-91.

Abstract

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 (< or = IC50) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacology
  • Cell Division / drug effects
  • DNA Methylation
  • DNA-Cytosine Methylases / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Flutamide / analogs & derivatives
  • Flutamide / pharmacology
  • Humans
  • Male
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Tumor Cells, Cultured

Substances

  • Androgens
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • 5,6-dihydro-5-azacytidine
  • hydroxyflutamide
  • Flutamide
  • DNA-Cytosine Methylases
  • Azacitidine