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The novel HSP90 inhibitor STA-1474 exhibits biologic activity against osteosarcoma cell lines.

Abstract
Osteosarcoma (OSA), the most common malignant bone tumor in dogs and children, exhibits a similar clinical presentation and molecular biology in both species. Unfortunately, 30-40% of children and 90% of dogs still die of disease despite aggressive therapy. The purpose of this study was to test the biologic activity of a novel heat shock protein 90 (HSP90) inhibitor, STA-1474, against OSA. Canine and human OSA cell lines and normal canine osteoblasts were treated with STA-1474 and evaluated for effects on proliferation (CyQuant), apoptosis (Annexin V, PARP cleavage, caspase 3/7 activation) and known HSP90 client proteins. HSP90 was immunoprecipitated from normal and malignant osteoblasts and Western blotting for co-chaperones was performed. Mice bearing canine OSA xenografts were treated with STA-1474, and tumors samples were evaluated for caspase-3 activation and loss of p-Akt/Akt. Treatment with STA-1474 promoted loss of cell viability, inhibition of cell proliferation and induction of apoptosis in OSA cell lines. STA-1474 and its active metabolite STA-9090 also demonstrated increased potency compared to 17-AAG. STA-1474 exhibited selectivity for OSA cells versus normal canine osteoblasts, and HSP90 co-precipitated with co-chaperones p23 and Hop in canine OSA cells but not in normal canine osteoblasts. Furthermore, STA-1474 downregulated the expression of p-Met/Met, p-Akt/Akt and p-STAT3. Finally, STA-1474 induced tumor regression, caspase-3 activation and downregulation of p-Met/Met and p-Akt/Akt in OSA xenografts. Together, these data suggest that HSP90 represents a relevant target for therapeutic intervention in OSA.
AuthorsJennifer K McCleese, Misty D Bear, Stacey L Fossey, Robert M Mihalek, Kevin P Foley, Weiwen Ying, James Barsoum, Cheryl A London
JournalInternational journal of cancer. Journal international du cancer (Int J Cancer) Vol. 125 Issue 12 Pg. 2792-801 (Dec 15 2009) ISSN: 1097-0215 [Electronic] United States
PMID19544563 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright (c) 2009 UICC.
Chemical References
  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • STA-1474
  • STAT3 Transcription Factor
  • Triazoles
  • Poly(ADP-ribose) Polymerases
  • Proto-Oncogene Proteins c-kit
  • Caspase 3
Topics
  • Animals
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Bone Neoplasms (drug therapy, metabolism, pathology)
  • Caspase 3 (metabolism)
  • Cell Cycle (drug effects)
  • Cell Proliferation (drug effects)
  • Dogs
  • Female
  • HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, SCID
  • Osteoblasts (drug effects, metabolism)
  • Osteosarcoma (drug therapy, metabolism, pathology)
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Proto-Oncogene Proteins c-kit (metabolism)
  • STAT3 Transcription Factor (metabolism)
  • Triazoles (pharmacology)
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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