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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-08-0130v1 16/2/401    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Festuccia, C. Articles by Bologna, M. Search for Related Content PubMed PubMed Citation Articles by Festuccia, C. Articles by Bologna, M.

C Festuccia, Experimental Medicine, University of L`Aquila, L`Aquila, 67100, Italy
G Gravina, Experimental Medicine, radiotherapy division, University of L`Aquila, L`aquila, Italy
A D`Alessandro, Biomedical Sciences and Technologies, university of L`aquila, L`aquila, Italy
P Muzi, Experimental Medicine, University of L`aquila, L`aquila, Italy
D Millimaggi, Experimental Medicine, University of L`Aquila, L`aquila, Italy
V Dolo, Experimental Medicine, University of L`Aquila, L`aquila, Italy
E Ricevuto, Experimental Medicine, University of L`Aquila, L`aquila, Italy
C Vicentini, Surgery, University of L`Aquila, L`aquila, Italy
M Bologna, basic and applied biology, University of L`aquila, L`aquila, Italy

Correspondence: Claudio Festuccia, Email: festucci{at}univaq.it

Abstract

One of the major obstacles in the treatment of HRPC is the development of chemoresistant tumors. The aim of this study is to evaluate the role of azacitidine as chemosensitizing agent in association with docetaxel and cispaltin using two models of aggressive prostate cancer, the 22rv1 and PC3 cell lines. Azacitidine shows anti proliferative effects associated with increased proportion of cells in G0/G1 and evident apoptosis in 22rv1 cells and increased proportion of cells in G2/M phase with absence of acute cell killing in PC3 cells. In vivo, azacitidine (0.8 mg/Kg ip) reduced tumor proliferation and induced apoptosis in both xenografts upmodulating the expression of p16INKA, Bax, Bak, p21/WAF1, and p27/KIP1, and inhibiting the activation of Akt activity and the expression of cyclin D1, Bcl-2 and Bcl-XL. In vitro treatments with azacitidine lead to upregulation of cleaved caspase 3 and PARP. BCl2 antagonists, such as HA-14-1, enhanced the effects of azacitidine in these two prostate cancer models. In addition, azacitidine showed synergistic effects with both docetaxel and cispaltin. In vivo this agent caused tumor growth delay without complete regression in xenograft systems. Azacitidine sensitized PC3 and 22rv1 xenografts to docetaxel and cispaltin treatments. These combinations were also tolerable in mice and superior to either agent alone. As docetaxel is the standard first-line chemotherapy for HRPC, the development of docetaxel-based combination therapies is of great interest in this disease stage. Our results provide a rationale for clinical trials on combination treatments with azacitidine in patients with hormone refractory and chemoresistant prostate tumors.