Inhibition of the insulin-like growth factor 1 receptor by CHM-1 blocks proliferation of glioblastoma multiforme cells.

Abstract

The insulin-like growth factor-1 receptor (IGF-1R) plays a pivotal role in transformation, growth, and survival of glioblastoma multiforme (GBM) cells, and has emerged as a general and promising target for cancer treatment. In this study, we examined the anti-tumor effects of CHM-1, a synthetic 6,7-methylenedioxy substituted 2-phenyl-4-quinolone derivative, on GBM cells in vitro and in vivo. CHM-1 selectively blocked IGF-1R auto-phosphorylation, with an ability to distinguish between IGF-1R and related tyrosine kinase receptors, such as insulin receptor (IR), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Further investigation revealed that, the phosphorylation of ERK1/2 as well as Akt was inhibited in CHM-1 treated GBM8401 cells possibly through the selective blockage of IGF-1R auto-phosphorylation. Our study also showed that p.o. treatment with the hydrophilic dihydrogen phosphate CHM-1P reduced the tumor volumes of the GBM8401 derived tumors in mouse brain and also prolonged the survival rate. The results provided potential opportunities for effective chemotherapy for GBM.

• Authors: Ying-Chao Lin, Shin-Chen Hou, Chao-Ming Hung, Jia-Ni Lin, Wei-Chih Chen, Chi-Tang Ho, Sheng-Chu Kuo, Tzong-Der Way
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 231 Pg. 119-26 (Apr 25 2015) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 25643584 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone
• Antineoplastic Agents
• Dioxoles
• Quinolones
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dioxoles (pharmacology, therapeutic use)
• Female
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice, Inbred BALB C
• Mice, SCID
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Quinolones (pharmacology, therapeutic use)
• Receptor, IGF Type 1 (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)