MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer

Molecular Cancer

Research

Mingxuan Xia¹  Kenneth Kolinsky¹  Lyubomir T Vassilev¹  Kathryn Packman¹  Christian Tovar¹  Brian Higgins¹  David C Heimbrook¹ 

[1] Discovery Oncology, Roche Research Center, Hoffmann-La Roche Inc, 07110, Nutley, NJ, USA;

关键词: Androgen;    Androgen Receptor;    LNCaP Cell;    Bicalutamide;    Androgen Receptor Expression;   

DOI  :  10.1186/1476-4598-10-49

 received in 2011-01-03, accepted in 2011-05-03,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundHormone therapy is the standard of care for newly diagnosed or recurrent prostate cancers. It uses anti-androgen agents, castration, or both to eliminate cancer promoting effect of testicular androgen. The p53 tumor suppressor controls a major pathway that can block cell proliferation or induce apoptosis in response to diverse forms of oncogenic stress. Activation of the p53 pathway in cancer cells expressing wild-type p53 has been proposed as a novel therapeutic strategy and recently developed MDM2 antagonists, the nutlins, have validated this in preclinical models of cancer. The crosstalk between p53 and androgen receptor (AR) signaling suggest that p53 activation could augment antitumor outcome of androgen ablation in prostate cancer. Here, we test this hypothesis in vitro and in vivo using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP.ResultsUsing charcoal-stripped serum as a cellular model of androgen deprivation, we show an increased apoptotic effect of p53 activation by nutlin-3a in the androgen-dependent LNCaP cells and to a lesser extent in androgen-independent but responsive 22Rv1 cell line. This effect is due, at least in part, to an enhanced downregulation of AR expression by activated p53. In vivo, androgen deprivation followed by two weeks of nutlin administration in LNCaP-bearing nude mice led to a greater tumor regression and dramatically increased survival.ConclusionsSince majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy.

【 授权许可】

Unknown   
© Tovar et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.