Autocrine vascular endothelial growth factor/vascular endothelial growth factor receptor-2 growth pathway represents a cyclooxygenase-2-independent target for the cyclooxygenase-2 inhibitor NS-398 in colon cancer cells.

Coexpression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) has been reported in tumor cells, suggesting the presence of an autocrine VEGF/VEGFR-2 growth pathway in solid tumors. Thus, we hypothesize that the presence of this autocrine pathway in colon cancer cells may be a COX-2-independent target of COX-2 inhibitors and a mechanism behind the antitumor effects of these agents. COX-2-positive (Caco2, HT-29) and COX-2-negative colon cancer cells (DLD-1, Hct-15) were used. Expression of VEGFR-2 was evaluated by Western blot and reverse transcriptase-polymerase chain reaction and VEGF production was measured from culture supernatant by enzyme-linked immunosorbent assay. Growth inhibition and the expression of VEGF and VEGFR-2 were compared after treatment with the COX-2 inhibitor, NS-398 at doses ranging from 5 to 100 microM. VEGF and VEGFR-2 were expressed in all four colon cancer cells and a blockade of VEGFR-2 with anti-VEGFR-2 antibody treatment induced growth inhibition of colon cancer cells, supporting the presence of autocrine VEGF/VEGFR-2 growth pathway. NS-398 suppressed the growth of colon cancer cells, independent of COX-2 expression. VEGFR-2 expression of tumor cells was reduced after NS-398 treatment at 100 microM, the concentration at which maximal growth inhibition was induced. The amount of VEGF in culture supernatant was increased by NS-398 at 100 microM, suggesting increased secretion of VEGF in compensation for reduced VEGFR-2 expression. The autocrine VEGF/VEGFR-2 growth pathway could be a COX-2-independent target of the COX-2 inhibitor, NS-398, in colon cancer cells.

Kim SJ ，Seo JH ，Lee YJ ，Yoon JH ，Choi CW ，Kim BS ，Shin SW ，Kim YH ，Kim JS ... -  《ONCOLOGY》

[Effects of selective cyclooxygenase-2 inhibitor NS-398 on 5-fluorouracil chemotherapy and progression of colon cells: an experimental study].

Zhang YC ，Wang S ，Zhang H ，Ye YJ ，Liang B ，Cui ZR ... -  《-》

The role of cyclooxygenase-2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer.

Cianchi F ，Cortesini C ，Schiavone N ，Perna F ，Magnelli L ，Fanti E ，Bani D ，Messerini L ，Fabbroni V ，Perigli G ，Capaccioli S ，Masini E ... -  《CLINICAL CANCER RESEARCH》

NS-398 inhibits tumor growth and liver metastasis of colon cancer through induction of apoptosis and suppression of the plasminogen activation system in a mouse model.

Nishikawa M ，Stapleton PP ，Freeman TA ，Gaughan JP ，Matsuda T ，Daly JM ... -  《JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS》

Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins.

Abdelrahim M ，Safe S 《MOLECULAR PHARMACOLOGY》