Anti-tumor activity of the HSP90 inhibitor SNX-2112 in pediatric cancer cell lines
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...
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| Published in: | Pediatric blood & cancer Vol. 58; no. 6; pp. 885 - 890 |
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| Format: | Journal Article |
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| 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 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. |
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| AbstractList | 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).
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.
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.
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. 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. |
| Author | Zwerdling, Theodore Chinn, Danielle C. Mack, Philip C. Yoon, Janet M. Holland, William S. |
| Author_xml | – sequence: 1 givenname: Danielle C. surname: Chinn fullname: Chinn, Danielle C. organization: Division of Hematology/Oncology, University of California Davis Cancer Center, Sacramento, CA – sequence: 2 givenname: William S. surname: Holland fullname: Holland, William S. organization: Division of Hematology/Oncology, University of California Davis Cancer Center, Sacramento, CA – sequence: 3 givenname: Janet M. surname: Yoon fullname: Yoon, Janet M. organization: Department of Pediatrics, University of California Davis, Sacramento, CA – sequence: 4 givenname: Theodore surname: Zwerdling fullname: Zwerdling, Theodore organization: Department of Pediatrics, University of California Davis, Sacramento, CA – sequence: 5 givenname: Philip C. surname: Mack fullname: Mack, Philip C. email: philip.mack@ucdmc.ucdavis.edu organization: Division of Hematology/Oncology, University of California Davis Cancer Center, Sacramento, CA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21796766$$D View this record in MEDLINE/PubMed |
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| CitedBy_id | crossref_primary_10_1016_j_bbrc_2014_05_076 crossref_primary_10_1158_1078_0432_CCR_15_1925 crossref_primary_10_3390_cells11162479 crossref_primary_10_3109_00498254_2013_853849 crossref_primary_10_1177_0300985816681409 crossref_primary_10_1007_s00432_014_1675_6 crossref_primary_10_3892_ijo_2014_2791 crossref_primary_10_1016_j_bbacli_2014_06_003 crossref_primary_10_3109_08923973_2015_1119159 crossref_primary_10_1007_s00432_014_1855_4 crossref_primary_10_1007_s00044_020_02534_3 crossref_primary_10_3892_or_2014_3552 crossref_primary_10_4155_fmc_2017_0011 crossref_primary_10_3390_cells10040754 crossref_primary_10_3389_fonc_2022_975088 |
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HSP90 plays a central role in stabilizing client proteins involved in malignant processes. SNX‐2112 is an orally administered potent HSP90 inhibitor... HSP90 plays a central role in stabilizing client proteins involved in malignant processes. SNX-2112 is an orally administered potent HSP90 inhibitor that has... |
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| SubjectTerms | 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 |
| Title | Anti-tumor activity of the HSP90 inhibitor SNX-2112 in pediatric cancer cell lines |
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