title: 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: Division of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan; Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan.
authors: Ying-Chao
authors: YC
authors: Lin
authors: Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan.
authors: Shin-Chen
authors: SC
authors: Hou
authors: Department of General Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; School of Medicine, I-Shou University, Kaohsiung, Taiwan.
authors: Chao-Ming
authors: CM
authors: Hung
authors: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors: Jia-Ni
authors: JN
authors: Lin
authors: The Ph.D. Program for Cancer Biology and Drug Discovery, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors: Wei-Chih
authors: WC
authors: Chen
authors: Department of Food Science, Rutgers University, New Brunswick, NJ, USA.
authors: Chi-Tang
authors: CT
authors: Ho
authors: Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, Taichung, Taiwan.
authors: Sheng-Chu
authors: SC
authors: Kuo
authors: Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan; Department of Health and Nutrition Biotechnology, College of Health Science, Asia University, Taichung, Taiwan. Electronic address: tdway@mail.cmu.edu.tw.
authors: Tzong-Der
authors: TD
authors: Way
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004149:Dioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C525063:2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone; D000970:Antineoplastic Agents; D004149:Dioxoles; D015363:Quinolones; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt
keywords: CHM-1; Glioblastoma multiforme; IGF-1R; Quinolone derivatives