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

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 10-100 nM. Low dose treatments (12 nM) resulted in a cytostatic response with a minimal increase in sub-G1 content. A higher dose (70 nM) 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.

• Authors: Danielle C Chinn, William S Holland, Janet M Yoon, Theodore Zwerdling, Philip C Mack
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 58 Issue 6 Pg. 885-90 (Jun 2012) ISSN: 1545-5017 [Electronic] United States
• PMID: 21796766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Heterocyclic Compounds, 4 or More Rings
• SNX 2112
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cisplatin (administration & dosage)
• Drug Synergism
• Flow Cytometry
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Hepatoblastoma
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Humans
• Lymphoma
• Neuroblastoma
• Osteosarcoma