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

Int J Cancer. 2009 Dec 15;125(12):2792-801. doi: 10.1002/ijc.24660.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology*
  • Caspase 3 / metabolism
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects*
  • Dogs
  • Female
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Immunoprecipitation
  • Mice
  • Mice, SCID
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteosarcoma / drug therapy
  • Osteosarcoma / metabolism
  • Osteosarcoma / 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


  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • STAT3 Transcription Factor
  • Triazoles
  • STA-1474
  • Poly(ADP-ribose) Polymerases
  • Proto-Oncogene Proteins c-kit
  • Caspase 3