Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma Journal Article

Authors: Ambati, S. R.; Lopes, E. C.; Kosugi, K.; Mony, U.; Zehir, A.; Shah, S. K.; Taldone, T.; Moreira, A. L.; Meyers, P. A.; Chiosis, G.; Moore, M. A. S.
Article Title: Pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor, alone and in combination with bortezomib in Ewing sarcoma
Abstract: Ewing sarcoma is characterized by multiple deregulated pathways that mediate cell survival and proliferation. Heat shock protein 90 (HSP90) is a critical component of the multi-chaperone complexes that regulate the disposition and activity of a large number of proteins involved in cell-signaling systems. We tested the efficacy of PU-H71, a novel HSP90 inhibitor in Ewing sarcoma cell lines, primary samples, benign mesenchymal stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis and reverse phase protein array in Ewing cell lines and invivo experiments in NSG and nude mice using the A673 cell line. We noted a significant therapeutic window in the activity of PU-H71 against Ewing cell lines and benign cells. PU-H71 treatment resulted in G2/M phase arrest. Exposure to PU-H71 resulted in depletion of critical proteins including AKT, pERK, RAF-1, c-MYC, c-KIT, IGF1R, hTERT and EWS-FLI1 in Ewing cell lines. Our results indicated that Ewing sarcoma tumor growth and the metastatic burden were significantly reduced in the mice injected with PU-H71 compared to the control mice. We also investigated the effects of bortezomib, a proteasome inhibitor, alone and in combination with PU-H71 in Ewing sarcoma. Combination index (CI)-Fa plots and normalized isobolograms indicated synergism between PU-H71 and bortezomib. Ewing sarcoma xenografts were significantly inhibited when mice were treated with the combination compared to vehicle or either drug alone. This provides a strong rationale for clinical evaluation of PU-H71 alone and in combination with bortezomib in Ewing sarcoma. © 2013 Federation of European Biochemical Societies.
Keywords: bortezomib; ewing sarcoma; pu-h71; hsp90 inhibitor
Journal Title: Molecular Oncology
Volume: 8
Issue: 2
ISSN: 1878-0261
Publisher: FEBS Press  
Date Published: 2014-03-01
Start Page: 323
End Page: 336
Language: English
DOI: 10.1016/j.molonc.2013.12.005
PROVIDER: scopus
PMCID: PMC3982393
PUBMED: 24388362
Notes: Export Date: 2 April 2014 -- Source: Scopus
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MSK Authors
  1. Andre L Moreira
    171 Moreira
  2. Srikanth Reddy Ambati
    27 Ambati
  3. Ahmet Zehir
    157 Zehir
  4. Gabriela Chiosis
    218 Chiosis
  5. Tony Taldone
    74 Taldone
  6. Paul Meyers
    247 Meyers
  7. Malcolm A S Moore
    427 Moore
  8. Ullas Mony
    6 Mony
  9. Smit Kamalkumar Shah
    8 Shah