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

作者：Chinn Danielle C; Holland William S; Yoon Janet M; Zwerdling Theodore; Mack Philip C^*

来源：Pediatric Blood and Cancer, 2012, 58(6): 885-890.

DOI：10.1002/pbc.23270

• developmental therapeutics
• molecular biology
• new agents
• pediatric oncology

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.

• 出版日期2012-6