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

• Published in: Pediatric blood & cancer Vol. 58; no. 6; pp. 885 - 890
• Main Authors: Chinn, Danielle C., Holland, William S., Yoon, Janet M., Zwerdling, Theodore, Mack, Philip C.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-06-2012
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Blotting, Western; Cell Cycle - drug effects; Cell Line, Tumor; Cisplatin - administration & dosage; developmental therapeutics; Drug Synergism; Flow Cytometry; Hepatoblastoma; Heterocyclic Compounds, 4 or More Rings - pharmacology; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; Lymphoma; molecular biology; Neuroblastoma; new agents; Osteosarcoma; pediatric oncology
• ISSN: 1545-5009; 1545-5017
• DOI: 10.1002/pbc.23270

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 IC50 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. Pediatr Blood Cancer 2012; 58: 885–890. © 2011 Wiley Periodicals, Inc.