title: The therapeutic potential of a novel non-ATP-competitive fibroblast growth factor receptor 1 inhibitor on gastric cancer.
abstract: Previous studies showed that fibroblast growth factor receptor 1 (FGFR1) is an attractive target in gastric cancer therapy. In the current study, we aimed to investigate whether the compound L6123, a novel non-ATP-competitive FGFR1 inhibitor, could show better antitumor activity than the leading compound, nordihydroguaiaretic acid (NDGA), in FGFR1-overexpressing gastric cancer cells. Using an MTT assay, we investigated the inhibitory effect of L6123 on the viability of three gastric cancer cells (MGC-803, SGC-7901, and BGC-823) overexpressing FGFR1, wild-type mouse embryonic fibroblast (MEF), and MEF expressing FGFR1, FGFR2, and FRS2α gene knockout (MEF). We studied the antitumor mechanism of L6123 against the gastric cancer cell line SGC-7901 by western blot analysis. The antitumor effects of L6123 on the gastric cancer cell line SGC-7901 were detected by flow cytometry, Hoechst staining, western blot analysis, and Transwell invasion assay. L6123 had lower IC50 in all three gastric cancer cells than NDGA and showed better inhibitory activity against MEF cells than against MEF cells. In the SGC-7901 gastric cell, L6123 inhibited the FGF2-induced phosphorylation of FGFR1/FRS2α/ERK1/2 in a dose-dependent manner, induced the activation of the apoptosis-related proteins, cleaved-PARP and cleaved-caspase-3, decreased the expression of pro-caspase-3 and Bcl-2, and induced tumor cell apoptosis. L6123 also dose-dependently reduced cell invasion ability, and showed better activity than NDGA at the same concentration. A novel non-ATP-competitive inhibitor L6123 showed excellent antigastric cancer activity by inhibiting the FGFR1 signaling pathway. Thus, we discovered a potential agent for the treatment of FGFR1-overexpressing gastric cancer.
authors.affiliation: aChemical Biology Research Center, College of Pharmaceutical Sciences bCollege of Information Science and Computer Engineering, Wenzhou Medical University Departments of cDigestive Diseases dEpidemiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China eThe Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas, USA.
authors.forename: Chaochao
authors.initials: C
authors.lastname: Xu
authors.forename: Wulan
authors.initials: W
authors.lastname: Li
authors.forename: Peihong
authors.initials: P
authors.lastname: Qiu
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Xia
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Du
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: Lailai
authors.initials: L
authors.lastname: Shen
authors.forename: Qiuxiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rong
authors.initials: R
authors.lastname: Jin
authors.forename: Jianzhang
authors.initials: J
authors.lastname: Wu
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D009637:Masoprocol / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D009637:Masoprocol; D051496:Receptor, Fibroblast Growth Factor, Type 1