Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation
Open accessAbstract
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.
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In a comparative analysis, a next-generation small molecule Hsp90 inhibitor EC154 more effectively inhibited HIF-1α and HIF-2α than 17-AAG.
“In a comparative analysis, a next-generation small molecule Hsp90 inhibitor EC154 more effectively inhibited HIF-1α and HIF-2α than 17-AAG (Bohonowych et al., 2011).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Bohonowych et al., 2011
The Abstract Results report that EC154 inhibited HIF at doses 10-fold lower than 17-AAG, and the Results section says EC154 reduced HIF-1α protein expression more effectively in UMRC2 cells. The claim overgeneralizes this comparison to HIF-2α: the paper reports cell-dependent effects on HIF-2α protein and greater suppression of HIF-driven transcripts by 17-AAG than EC154 in 786-O cells. (LLM, conf=0.88)
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- Authors
- Bohonowych, J. E., Peng, S., Gopal, U., Hance, M. W., Wing, S. B., Argraves, K. M., Lundgren, K., & Isaacs, J. S.
- Affiliations
- Medical University of South Carolina (US)
- Central South University (CN)
- Biogen (United States) (US)
- Corresponding author
- Isaacs, Jennifer S
- Venue
- BMC Cancer
- Published
- 2011-12
- Volume
- 11
- Issue
- 1
- Pages
- 520-520
- ISSN
- 1471-2407 (ISSN-L)
- PMC
- PMC3259130
- OpenAlex
- W2010672293
- Cited by
- 32
- References
- 98
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 1 · 2015: 2 · 2014: 3 · 2013: 4 · 2012: 1
- FWCI
- 1.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Cancer (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Biogen
- IC Design Education Center
- National Institutes of Health (5k22ca107212-03, 5p20rr016461-11, K12GM081265, RR016461)
- National Heart, Lung, and Blood Institute (HL80404, R01HL080404)
- National Cancer Institute (K22 CA107212-01)
- National Center for Research Resources (RR107677, P 20 RR-016461)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Keywords
- Hsp90 inhibitors, clear cell renal cell carcinoma, 17-AAG, panobinostat, histone deacetylase inhibitors, HIF-1, HIF-2, angiogenesis, endothelial barrier function, cell motility
- MeSH terms
- Panobinostat, Antineoplastic Agents, Carcinoma, Renal Cell, Cell Movement, Cell Survival, Humans, Hydroxamic Acids, Indoles, Kidney Neoplasms, Luciferases, Neoplasm Proteins, Transcription, Genetic, Blotting, Western, Electric Impedance, Disease Progression, HSP90 Heat-Shock Proteins, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Hypoxia-Inducible Factor 1, Real-Time Polymerase Chain Reaction
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