title: Green tea (-)-epigalocatechin-3-gallate inhibits KIT activity and causes caspase-dependent cell death in gastrointestinal stromal tumor including imatinib-resistant cells.
abstract: Imatinib, a selective tyrosine kinase inhibitor, has been used as a standard first-line therapy for gastrointestinal stromal tumor (GIST) patients. Unfortunately, most patients responding to imatinib will eventually exhibit the resistance, the cause of which is not fully understood. The serious clinical problems of imatinib-resistance demand alternative treatment strategy. (-)-Epigallocatechin-3-gallate (EGCG), a main component of green tea catechin, has been demonstrated potential anti-tumor effects on various types of cancer cells. Here, we report for the first time that EGCG has shown anti-tumor effects on gastrointestinal stromal tumor cell line GIST-T1 by suppressing cell proliferation and eventually inducing cell death via caspase-dependent pathways. GIST-T1 and imatinib resistant GIST-T1 (GIST-T1 IR) cells were used to assess the effects of EGCG. In both cell types, KIT activity was completely inhibited after 4 h treatment with 60 muM EGCG. EGCG specifically inhibited activated KIT, which was demonstrated by using Ba/F3 cells transfected with human wild-type KIT construct. At a dose of 30 muM EGCG, the KIT activity remains but at more than 40 muM EGCG, the KIT activity was abolished in these transfected-Ba/F3 cells. Our results suggest that EGCG has a promising potential as a natural KIT inhibitor and therefore it could be used as a novel therapeutic or preventive reagent for GISTs including the imatinib-resistant cases.
authors.affiliation: Division of Ultrafine Structure, Department of Pathology, Research Institute of International Medical Center of Japan, Tokyo, Japan.
authors.forename: Hoang Thanh
authors.initials: HT
authors.lastname: Chi
authors.forename: Hoang Anh
authors.initials: HA
authors.lastname: Vu
authors.forename: Reo
authors.initials: R
authors.lastname: Iwasaki
authors.forename: Le Ba
authors.initials: le B
authors.lastname: Thao
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hara
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sato
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D013662:Tea / Q000737:chemistry*; D013997:Time Factors
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013662:Tea; D000068877:Imatinib Mesylate; D002392:Catechin; C045651:epigallocatechin gallate; D019009:Proto-Oncogene Proteins c-kit; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases