title: Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation.
abstract: BACKGROUND
  Perturbing 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.
  
  
  METHODS
  Here 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Jessica E S
authors.initials: JE
authors.lastname: Bohonowych
authors.forename: Shuping
authors.initials: S
authors.lastname: Peng
authors.forename: Udhayakumar
authors.initials: U
authors.lastname: Gopal
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hance
authors.forename: Shane B
authors.initials: SB
authors.lastname: Wing
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Argraves
authors.forename: Karen
authors.initials: K
authors.lastname: Lundgren
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Isaacs
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D017097:Electric Impedance; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077767:Panobinostat; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D006877:Hydroxamic Acids; D051793:Hypoxia-Inducible Factor 1; D007211:Indoles; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; D000077767:Panobinostat; D008156:Luciferases