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.
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Authors | Kuan-Tin Chen, Mann-Jen Hour, Shih-Chang Tsai, Jing-Gung Chung, Sheng-Chu Kuo, Chi-Cheng Lu, Yu-Jen Chiu, Yi-Hsuan Chuang, Jai-Sing Yang |
Journal | International journal of oncology
(Int J Oncol)
Vol. 39
Issue 3
Pg. 611-9
(Sep 2011)
ISSN: 1791-2423 [Electronic] Greece |
PMID | 21667022
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline
- Matrix Metalloproteinase Inhibitors
- Quinazolines
- RNA, Messenger
- Receptor, IGF Type 1
- Oncogene Protein v-akt
- p38 Mitogen-Activated Protein Kinases
- MAP Kinase Kinase 4
- Matrix Metalloproteinase 2
- Matrix Metalloproteinase 9
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Topics |
- Bone Neoplasms
(drug therapy, metabolism, pathology)
- Cell Line, Tumor
- Cell Movement
(drug effects)
- Humans
- MAP Kinase Kinase 4
(metabolism)
- Matrix Metalloproteinase 2
(genetics, metabolism)
- Matrix Metalloproteinase 9
(genetics, metabolism)
- Matrix Metalloproteinase Inhibitors
- Models, Molecular
- Molecular Targeted Therapy
- Neoplasm Metastasis
- Oncogene Protein v-akt
(metabolism)
- Osteosarcoma
(drug therapy, metabolism, pathology)
- Phosphorylation
(drug effects)
- Quinazolines
(pharmacology)
- RNA, Messenger
(biosynthesis, genetics)
- Real-Time Polymerase Chain Reaction
- Receptor, IGF Type 1
(antagonists & inhibitors, metabolism)
- Signal Transduction
(drug effects)
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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