Document Detail


5-Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors.
MedLine Citation:
PMID:  20333699     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Prostate     Volume:  70     ISSN:  1097-0045     ISO Abbreviation:  Prostate     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-26     Completed Date:  2010-08-26     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8101368     Medline TA:  Prostate     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1166-78     Citation Subset:  IM    
Copyright Information:
(c) 2010 Wiley-Liss, Inc.
Affiliation:
Division of Radiotherapy, Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. giovanniluca.gravina@poste.it
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MeSH Terms
Descriptor/Qualifier:
Androgen Antagonists / administration & dosage,  pharmacology*
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 / antagonists & inhibitors,  biosynthesis*
Tosyl Compounds / administration & dosage,  pharmacology*
Chemical
Reg. No./Substance:
0/AR protein, human; 0/Androgen Antagonists; 0/Anilides; 0/Nitriles; 0/Receptors, Androgen; 0/Tosyl Compounds; 320-67-2/Azacitidine; 90357-06-5/bicalutamide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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