RRC ID 51713
Author Nam AR, Kim JW, Park JE, Bang JH, Jin MH, Lee KH, Kim TY, Han SW, Im SA, Kim TY, Oh DY, Bang YJ.
Title Src as a Therapeutic Target in Biliary Tract Cancer.
Journal Mol. Cancer Ther.
Abstract Src, a nonreceptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using 9 human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib. Bosutinib abrogated phosphorylation of Src and its downstream molecules, and significantly increased G1 cell-cycle arrest and apoptosis. Bosutinib significantly inhibited cell migration and invasion and decreased epithelial-mesenchymal transition markers. Bosutinib combined with gemcitabine or cisplatin showed synergistic antiproliferative and antimigratory effects. In addition, this combination further inhibited phosphorylation of Src and its downstream molecules and decreased epithelial-mesenchymal transition marker expression compared with bosutinib alone. We established a SNU-478 xenograft model for in vivo experiments, because SNU-478 was more tumorigenic than SNU-308. Bosutinib combined with gemcitabine or cisplatin showed significantly more potent antitumor effects than bosutinib alone. Bosutinib combined with gemcitabine further decreased Ki-67 expression and Src phosphorylation, and further increased TUNEL expression. Our data suggest that Src might be a potential therapeutic target in BTC. Bosutinib demonstrated promising antitumor activity alone or in combination with gemcitabine or cisplatin in BTC cells, which supports further clinical development in patients with advanced BTC. Mol Cancer Ther; 15(7); 1515-24. ©2016 AACR.
Volume 15(7)
Pages 1515-24
Published 2016-7
DOI 10.1158/1535-7163.MCT-16-0013
PII 1535-7163.MCT-16-0013
PMID 27196758
MeSH Aniline Compounds / pharmacology Animals Antineoplastic Agents / pharmacology* Apoptosis / drug effects Biliary Tract Neoplasms / drug therapy Biliary Tract Neoplasms / metabolism* Biliary Tract Neoplasms / pathology Cell Cycle / drug effects Cell Line, Tumor Cell Movement / drug effects Cell Proliferation / drug effects Disease Models, Animal Female Humans Mice Molecular Targeted Therapy Nitriles / pharmacology Phosphorylation Protein Kinase Inhibitors / pharmacology* Quinolines / pharmacology Signal Transduction / drug effects Xenograft Model Antitumor Assays src-Family Kinases / antagonists & inhibitors*
IF 4.856
Human and Animal Cells HuCCT1(RCB1960) TFK-1(RCB2537)