Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation

BMC Cancer

Research Article

Karen Lundgren¹  Shuping Peng²  Michael W Hance³  Jessica ES Bohonowych³  Udhayakumar Gopal³  Jennifer S Isaacs³  Shane B Wing⁴  Kelley M Argraves⁴ 

[1] Biogen Idec, San Diego, CA, USA;Cancer Research Institute, Central South University, Changsha, China;Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA;Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA;

关键词: Hypoxia Inducible Factor;    Clear Cell Renal Cell Carcinoma Cell;    Hsp90 Inhibitor;    Clear Cell Renal Cell Carcinoma;    Human Umbilical Vascular Endothelial Cell;   

DOI  :  10.1186/1471-2407-11-520

 received in 2011-06-24, accepted in 2011-12-15,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundPerturbing Hsp90 chaperone function targets hypoxia inducible factor (HIF) function in a von Hippel-Lindau (VHL) independent manner, and represents an approach to combat the contribution of HIF to cell renal carcinoma (CCRCC) progression. However, clinical trials with the prototypic Hsp90 inhibitor 17-AAG have been unsuccessful in halting the progression of advanced CCRCC.MethodsHere we evaluated a novel next generation small molecule Hsp90 inhibitor, EC154, against HIF isoforms and HIF-driven molecular and functional endpoints. The effects of EC154 were compared to those of the prototypic Hsp90 inhibitor 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589.ResultsThe findings indicate that EC154 is a potent inhibitor of HIF, effective at doses 10-fold lower than 17-AAG. While EC154, 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589 impaired HIF transcriptional activity, CCRCC cell motility, and angiogenesis; these effects did not correlate with their ability to diminish HIF protein expression. Further, our results illustrate the complexity of HIF targeting, in that although these agents suppressed HIF transcripts with differential dynamics, these effects were not predictive of drug efficacy in other relevant assays.ConclusionsWe provide evidence for EC154 targeting of HIF in CCRCC and for LBH589 acting as a suppressor of both HIF-1 and HIF-2 activity. We also demonstrate that 17-AAG and EC154, but not LBH589, can restore endothelial barrier function, highlighting a potentially new clinical application for Hsp90 inhibitors. Finally, given the discordance between HIF activity and protein expression, we conclude that HIF expression is not a reliable surrogate for HIF activity. Taken together, our findings emphasize the need to incorporate an integrated approach in evaluating Hsp90 inhibitors within the context of HIF suppression.

【 授权许可】

Unknown   
© Bohonowych 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.