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

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

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  • 1Division of Radiotherapy, Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. giovanniluca.gravina@poste.it

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.

(c) 2010 Wiley-Liss, Inc.

PMID:
20333699
[PubMed - indexed for MEDLINE]
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