title: Lapatinib, a dual inhibitor of EGFR and HER2, has synergistic effects             with 5-fluorouracil on esophageal carcinoma.
abstract: Epidermal growth factor receptor (EGFR) and human epidermal growth factor             receptor 2 (HER2) amplification occurs in over 30% of esophageal carcinomas. Combination             therapies with EGFR and HER2-targeting agents and cytotoxic agents are considered             a potential therapeutic option for esophageal cancer. We evaluated the antitumor             effects of lapatinib, a dual tyrosine kinase inhibitor which simultaneously inhibits             EGFR and HER2, 5-fluorouracil (5-Fu) alone and in combination on esophageal cancer             cells. The antiproliferative activity of lapatinib, 5-Fu and lapatinib plus 5-Fu             was measured by MTT assay and the combination index (CI) values were calculated.             Additionally, cell cycle distribution of lapatinib alone and the combination with             5-Fu were detected by flow cytometry analysis. Annexin V-FITC and propidium iodide             stain were used for analyzing the apoptotic cells after cells were treated with             either agent alone or in combination. The EGFR and HER2 activated signaling pathways             were monitored by western blotting. The combination of lapatinib and 5-Fu synergistically             inhibited cell proliferation and exhibited an enhanced proapoptotic effect on             esophageal cancer cells. The potentiation effect of combined treatment was associated             with downregulation of EGFR and HER2 signaling pathways because data from western             blot analysis showed that lapatinib in combination with 5-Fu markedly reduced             the phosphorylation of EGFR and HER2, and inhibited the activation of downstream             signaling molecules, such as AKT and ERK. A significant G1 arrest was also observed             in cell cycle analysis after exposing cells to lapatinib, however, combination             with 5-Fu did not enhance G1 arrest. These results indicate that the combination             of the lapatinib and 5-Fu is a promising treatment option for esophageal carcinoma             with HER2 amplification.
authors.affiliation: Xinxiang Medical University, The First Affiliated Hospital of Xingiang Medical University, Henan Province, PR China. guoxiaofang_1981@126.com
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Guo
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zhu
authors.forename: Gen-Shen
authors.initials: GS
authors.lastname: Zhong
authors.forename: Bao-Guo
authors.initials: BG
authors.lastname: Deng
authors.forename: Zhi-Tao
authors.initials: ZT
authors.lastname: Gao
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005784:Gene Amplification; D006801:Humans; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D005472:Fluorouracil; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases