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

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.

• Authors: Giovanni Luca Gravina, Francesco Marampon, Mario Di Staso, Pierluigi Bonfili, Alessandro Vitturini, Emmanuele A Jannini, Richard G Pestell, Vincenzo Tombolini, Claudio Festuccia
• Journal: The Prostate (Prostate) Vol. 70 Issue 11 Pg. 1166-78 (Aug 2010) ISSN: 1097-0045 [Electronic] United States
• PMID: 20333699 (Publication Type: Journal Article)
• Copyright: (c) 2010 Wiley-Liss, Inc.

Chemical References

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

Topics

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