5-Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors

Prostate. 2010 Aug;70(11):1166-78. doi: 10.1002/pros.21151.

Abstract

Background: Epigenetic modifications play a key role in the in prostate cancer (Pca) progression to a hormone refractory state (HRPC) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research. In this regard, 5-Azacitine (5-Aza) represents a promising epigenetic modulator. This study tested the hypothesis that 5-Aza may restore and enhance the responsiveness of HRPC cells to anti-hormonal therapy on Androgen receptor (AR) expressing (22rv1) and AR-deficient (PC3) cells.

Methods: The effects were studied in vitro and in vivo models. This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines.

Results: This combined treatment up-regulated the expression of FasL, phospho-FADD, p16(INKA), Bax, Bak, and p21(WAF1), and inhibited FLIP, Bcl-2, and Bcl-XL expression. The re-activation of hormonal response of AR-negative PC3 cell line was partially due to the AR re-expression mediated by 5-Aza treatment. In contrast, the increase in the response to anti-androgenic therapy in 22rv1 did not correlate with AR expression levels. Furthermore, xenograft studies revealed that the combined treatment of 5-Aza with AR-antagonist Bicalutamide had additive/synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis.

Conclusions: So, this study strongly suggests a therapeutic potential of 5-Aza in combination with anti-androgen therapy in patients with in AR expressing and AR-deficient HRPC.

MeSH terms

  • Androgen Antagonists / administration & dosage
  • Androgen Antagonists / pharmacology*
  • Androgen Receptor Antagonists
  • Anilides / administration & dosage
  • Anilides / pharmacology*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Azacitidine / administration & dosage
  • Azacitidine / pharmacology*
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Drug Synergism
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasms, Experimental
  • Neoplasms, Hormone-Dependent / drug therapy*
  • Neoplasms, Hormone-Dependent / metabolism
  • Neoplasms, Hormone-Dependent / pathology
  • Nitriles / administration & dosage
  • Nitriles / pharmacology*
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Random Allocation
  • Receptors, Androgen / biosynthesis*
  • Tosyl Compounds / administration & dosage
  • Tosyl Compounds / pharmacology*

Substances

  • AR protein, human
  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Anilides
  • Nitriles
  • Receptors, Androgen
  • Tosyl Compounds
  • bicalutamide
  • Azacitidine