Anti-tumor activity of the HSP90 inhibitor SNX-2112 in pediatric cancer cell lines

Danielle C. Chinn, William S. Holland, Janet M. Yoon, Theodore Zwerdling, Philip Mack

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Background: HSP90 plays a central role in stabilizing client proteins involved in malignant processes. SNX-2112 is an orally administered potent HSP90 inhibitor that has demonstrated pre-clinical anti-tumor activity in adult malignancies. As many childhood tumors depend upon HSP90 client proteins, we sought to test the pre-clinical efficacy of SNX-2112 in a panel of pediatric cancer cell lines both as a single-agent and in combination with cisplatin (CP). Procedure: Eight cell lines (from osteosarcoma, neuroblastoma, hepatoblastoma, and lymphoma) were studied. Short- and long-term effects of SNX-2112 were assessed by MTT and clonogenic assays. Cell cycling was measured using flow cytometry. Status of HSC70, HSP72, AKT1, C-Raf, and PARP was assessed by immunoblotting. Efficacy of SNX-2112 in combination with CP was assessed using median-effect analysis. Results: Cell lines studied demonstrated sensitivity to SNX-2112 with IC 50 values ranging from 10-100nM. Low dose treatments (12nM) resulted in a cytostatic response with a minimal increase in sub-G1 content. A higher dose (70nM) exhibited a more prolonged inhibition and larger sub-G1 accumulation. Observed levels of AKT1 and C-Raf were markedly reduced over time along with an increase in PARP cleavage. In concurrently administered combination treatments, SNX-2112 and CP synergistically inhibited cell growth. Conclusions: SNX-2112 showed marked single-agent activity in pediatric cancer cell lines with downstream effects on HSP90 client proteins. The combination of SNX-2112 and CP showed synergistic activity in two cell lines tested. Further studies of HSP90 inhibitors such as SNX-2112 as a single agent or in combination with chemotherapy are warranted in pediatric cancer.

Original languageEnglish (US)
Pages (from-to)885-890
Number of pages6
JournalPediatric Blood and Cancer
Issue number6
StatePublished - Jun 2012


  • Developmental therapeutics
  • Molecular biology
  • New agents
  • Pediatric oncology

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology


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