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 journalArticle

12 Citations (Scopus)

Abstract

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
Volume58
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Pediatrics
Cell Line
Neoplasms
Cisplatin
Hepatoblastoma
SNX 2112
Proteins
Cytostatic Agents
Osteosarcoma
Combination Drug Therapy
Neuroblastoma
Immunoblotting
Lymphoma
Flow Cytometry
Therapeutics
Growth

Keywords

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

ASJC Scopus subject areas

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

Cite this

Anti-tumor activity of the HSP90 inhibitor SNX-2112 in pediatric cancer cell lines. / Chinn, Danielle C.; Holland, William S.; Yoon, Janet M.; Zwerdling, Theodore; Mack, Philip.

In: Pediatric Blood and Cancer, Vol. 58, No. 6, 06.2012, p. 885-890.

Research output: Contribution to journalArticle

Chinn, Danielle C. ; Holland, William S. ; Yoon, Janet M. ; Zwerdling, Theodore ; Mack, Philip. / Anti-tumor activity of the HSP90 inhibitor SNX-2112 in pediatric cancer cell lines. In: Pediatric Blood and Cancer. 2012 ; Vol. 58, No. 6. pp. 885-890.
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N2 - 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.

AB - 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.

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