title: The green tea polyphenol EGCG potentiates the antiproliferative activity of sunitinib in human cancer cells.
abstract: Sunitinib is a promising drug for clinical applications; however, the efficacy is reduced by the feedback activation of many signaling cascades. In this study, we investigated the ability of (-)-epigallocatechin-3-gallate (EGCG) to synergize with sunitinib and inhibit insulin receptor substrate (IRS)/mitogen-activated protein kinase (MAPK) pathway activation. MCF-7, H460, and H1975 cell lines with PIK3CA mutations were treated with sunitinib or mock treated 0-24 h and then pulsed with 0-50 μM EGCG for another 12 h; cell proliferation and vascular endothelial growth factor (VEGF) secretion were then evaluated. To analyze angiogenesis and VEGF levels in vivo, MCF-7 and H460 xenograft tumors were established. Cell growth signaling cascades were assessed via western blotting in vitro, and tumors were subjected to immunohistochemical analyses to evaluate signaling cascades in vivo. EGCG enhanced the antiproliferation and VEGF secretion-reducing effects of sunitinib in the three tested cell lines. In vivo, EGCG administration at 4 h after sunitinib treatment resulted in greater tumor shrinkage and antiangiogenesis than with sunitinib alone. We further demonstrated that sunitinib exposure induces insulin receptor substrate-1 (IRS-1) upregulation and activation of MAPK signaling. More strikingly, EGCG treatment downregulated IRS-1 levels and suppressed mitogenic effects. In vivo, immunohistochemical analyses demonstrated marked suppression of the IRS/MAPK/p-S6K1 signaling cascade by EGCG, especially after sunitinib treatment. EGCG potentially synergizes with sunitinib due to its ability to suppress the IRS/MAPK signaling induced by sunitinib. We conclude that administration of EGCG after sunitinib treatment represents a promising strategy for the treatment of cancer.
authors.affiliation: Department of Medical Oncology, Cancer Center, The State Key Laboratory of Biotherapy, West China Medical School, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medical Oncology, Cancer Center, The State Key Laboratory of Biotherapy, West China Medical School, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Medical Oncology, Cancer Center, The State Key Laboratory of Biotherapy, West China Medical School, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Medical Oncology, Cancer Center, The State Key Laboratory of Biotherapy, West China Medical School, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ding
authors.affiliation: Department of Medical Oncology, Cancer Center, The State Key Laboratory of Biotherapy, West China Medical School, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan Province, China. doctorzhouyi2@163.com.
authors.forename: Ji-Yan
authors.initials: JY
authors.lastname: Liu
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011379:Prognosis; D011758:Pyrroles / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D000077210:Sunitinib; D013662:Tea / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D055504:Insulin Receptor Substrate Proteins; D011758:Pyrroles; D013662:Tea; D042461:Vascular Endothelial Growth Factor A; D002392:Catechin; C045651:epigallocatechin gallate; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D020928:Mitogen-Activated Protein Kinases; D000077210:Sunitinib
keywords: Catechin; Feedback; Insulin receptor substrate proteins; MAP kinase signaling system; Pyrroles