ICEECE2012 Poster Presentations Endocrine tumours and neoplasia (112 abstracts)
Histone deacetylase inhibitor belinostat (PXD-101) represses androgen receptor expression and acts synergistically with castration and bicalutamide treatment to inhibit prostate cancer growth in hormone refractory models
C. Festuccia 1 , G. Gravina 1, , F. Marampon 1 , P. Muzi 1 , A. Mancini 1 , M. Piccolella 3 , P. Negri-Cesi 3 , M. Motta 3 , V. Tobolini 2 , A. Lenzi 1 & E. Jannini 2
University of Milano, Milano, Italy.
Rationale and aims: Aberrant activation or “reactivation” of androgen receptor in the course of androgen-ablation therapy shows a potential cause for the development of castration-resistant prostate cancer. This study tested the hypothesis that belinostat (PXD101), a potent pan histone deacetylase inhibitor, may potentiate hormonal therapy and prevent onset of castration resistant phenotype Material and Methods. A panel of human prostate cancer (Pca) cells with graded castration resistant phenotype and in vivo models were used to verify this hypothesis.
Results: In this report we demonstrated that hormonal manipulation favors the onset of castration-resistant phenotype by the increase of HDAC expression and activity as well as by the increased expression and activity of AR, EGFR, HER2 and Akt. Consistent with these observations, the functional knockdown of HDACs by Belinostat prevented the onset of castration resistant phenotype with a significant down-regulation of AR, EGFR, HER2 and Akt expression/activity. The deregulation of functional cooperation between HDAC-6 with hsp90, on one hand, and between GSK-3beta with CRM1, on the other hand, may explain the biological effects of Belinostat. In this regard, the HDAC-6 silencing or the functional knockdown of hsp90 by 17AAG resulted in the selective down-regulation of AR, EGFR, HER2 and Akt expression/activity, while the decreased p-GSK-3beta expression after Belinostat treatment increased the nuclear expression of CRM1 which in turn modified the AR and survivin recycling with increased caspase-3 activity.
Conclusions: HDAC inhibitors retain the ability to prevent the onset of castration resistant phenotype and, therefore, merit clinical investigation in this setting. However, further information are necessary to develop clinical treatment strategies for this disease stages.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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