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

  • 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
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  • Published online on: Wednesday, June 8, 2011
  • Pages: 611-619
  • DOI: 10.3892/ijo.2011.1071

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.
Journal Cover

September 2011
Volume 39 Issue 3

Print ISSN: 1019-6439
Online ISSN:1791-2423

2012 Impact Factor: 2.773
Ranked #30/202 Oncology
(total number of cites)

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APA
Chen, K., Hour, M., Tsai, S., Chung, J., Kuo, S., Lu, C., Chiu, Y., Chuang, Y., & Yang, J. (2011). 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. International Journal of Oncology, 39(3), 611-619.
MLA
Chen, Hour, Tsai, Chung, Kuo, Lu, Chiu, Chuang, and Jai-Sing Yang. "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." International Journal of Oncology International Journal of Oncology 39.3 (2011): 611-619.
Chicago
Chen, Hour, Tsai, Chung, Kuo, Lu, Chiu, Chuang, and Jai-Sing Yang. "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." International Journal of Oncology International Journal of Oncology 39 no. 3 (2011): 611-619.