Premium
5‐azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors
Author(s) -
Gravina Giovanni Luca,
Marampon Francesco,
Di Staso Mario,
Bonfili Pierluigi,
Vitturini Alessandro,
Jannini Emmanuele A.,
Pestell Richard G.,
Tombolini Vincenzo,
Festuccia Claudio
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21151
Subject(s) - bicalutamide , androgen receptor , cancer research , prostate cancer , in vivo , apoptosis , fadd , epigenetics , androgen , azacitidine , medicine , chemistry , endocrinology , biology , cancer , hormone , programmed cell death , dna methylation , gene expression , biochemistry , microbiology and biotechnology , gene , caspase
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. Prostate 70: 1166–1178, 2010. © 2010 Wiley‐Liss, Inc.