title: The novel synthesized 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) compound exhibits anti-metastatic effects in human osteosarcoma U-2 OS cells through targeting insulin-like growth factor-I receptor.
abstract: Our previous study demonstrated that 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) possesses potential anticancer activity and exhibits greater antitumor effect than the other quinazoline compounds in human osteogenic sarcoma U-2 OS cells via in vitro screening. In this study, we focused on investigating the anti-metastatic activity and the signaling pathways involved in LJJ-10 action in U-2 OS cells. The results from wound healing and Boyden chamber transwell assays indicated that LJJ-10 exhibited an inhibitory effect on the migration and invasion of U-2 OS cells. LJJ-10 also inhibited matrix metalloproteinase-2 (MMP-2) and MMP-9 enzyme activities and caused a concentration-dependent decrease in protein levels by gelatin zymography assay and Western blot analysis, respectively. Meanwhile, LJJ-10 suppressed MMP-2 and MMP-9 mRNA levels in a concentration-dependent fashion after 12-h exposure in U-2 OS cells. Computational modeling showed that LJJ-10 is bound into the IGF-1R via hydrophobic interactions with Leu975, Val983, Ala1001, Glu1050 and Met1052 with one hydrogen bond between 6-F and Met1052. LJJ-10 reduced the protein levels of p-JNK, p-p38, p-ERK, p-AKT and p-IGFR by Western blotting and these influences are concentration-dependent. Based on these observations, this study suggests that molecular targeting of the insulin-like growth factor-I receptor (IGF-1R) signaling leads to the suppression of downstream MAPK/AKT signaling and downregulation of MMP-2 and -9 RNA levels and protein levels in LJJ-10-treated U-2 OS cells. Therefore, the inhibition of metastasis in human osteosarcoma cells by treatment with this novel agent, LJJ-10 may be a useful chemotherapeutic approach.
authors.affiliation: Department of Pharmacology, China Medical University, Taichung 404, Taiwan, ROC.
authors.forename: Kuan-Tin
authors.initials: KT
authors.lastname: Chen
authors.forename: Mann-Jen
authors.initials: MJ
authors.lastname: Hour
authors.forename: Shih-Chang
authors.initials: SC
authors.lastname: Tsai
authors.forename: Jing-Gung
authors.initials: JG
authors.lastname: Chung
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Lu
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chiu
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Chuang
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
mesh_terms: D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D051058:Oncogene Protein v-akt / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C569175:6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline; D061965:Matrix Metalloproteinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D017526:Receptor, IGF Type 1; D051058:Oncogene Protein v-akt; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9