The heat shock protein 90 inhibitor SNX-2112 inhibits B16 melanoma cell growth in vitro and in vivo.

Abstract

SNX-2112 is a selective heat shock protein 90 (Hsp90) inhibitor which can exert a potent anticancer activity. In this study, we investigated the effects of SNX-2112 on B16 melanoma cells in vitro and in vivo. The 3-(4,5-dimetrylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis demonstrated that SNX-2112 dose-dependently inhibited the growth of B16 cells, and induced G0/G1 cell cycle arrest and apoptosis. Western blotting revealed that SNX-2112 lead to the degradation of Hsp90 client proteins including Akt, IKKα, NF-κB, B-Raf and GSK3β. Furthermore, we assessed the antitumor effect of SNX-2112 in vivo, using a xenograft model in C57BL/6 mice. Oral administration of SNX-2112 significantly inhibited the growth of B16 tumors in mice, with a 47% inhibition observed at dose of 80 mg/kg/day for 15 days, compared to control tumors. Hematoxylin-eosin (H&E) staining of xenograft tissues showed that SNX-2112 also inhibited angiogenesis and lead to a lower blood vessel density in the tumors, compared to the control group. These findings demonstrate that SNX-2112 can exhibit a potent anticancer activity against B16 melanoma cells both in vitro and in vivo, by inhibiting cell proliferation and inducing cell cycle arrest and apoptosis in a mechanism dependent on the degradation of Hsp90 client proteins.

• Authors: Kai-Sheng Liu, Wei-Chao Ding, Shao-Xiang Wang, Zhong Liu, Guo-Wen Xing, Ying Wang, Yi-Fei Wang
• Journal: Oncology reports (Oncol Rep) Vol. 27 Issue 6 Pg. 1904-10 (Jun 2012) ISSN: 1791-2431 [Electronic] Greece
• PMID: 22447251 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Heterocyclic Compounds, 4 or More Rings
• NF-kappa B
• SNX 2112
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Chuk protein, mouse
• I-kappa B Kinase
• Mitogen-Activated Protein Kinases
• Glycogen Synthase Kinase 3

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Glycogen Synthase Kinase 3 beta
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• I-kappa B Kinase (antagonists & inhibitors)
• Melanoma, Experimental (drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinases (antagonists & inhibitors)
• NF-kappa B (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Xenograft Model Antitumor Assays