Molecular mechanism of the inhibitory effect of KS-5 on bFGF-induced angiogenesis in vitro and in vivo
Journal
Cancer Letters
Journal Volume
263
Journal Issue
1
Pages
114-121
Date Issued
2008
Author(s)
CHE-MING TENG
Abstract
Inhibition of angiogenesis controls the expansion and metastasis of many solid tumors and other related-diseases. KS-5 (1,7-dihydroxy-3-methoxyacridone), is an inactive analogue of the substituted 1-hydroxy acridone antiviral class. This study aimed at studying the effects of KS-5 on bFGF-induced angiogenesis in cultured human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. KS-5 inhibited bFGF (10 ng/ml)-induced cell proliferation in a concentration-dependent manner, but did not exhibit significant cytotoxic effect examined by LDH release assay. KS-5 inhibited bFGF-induced angiogenesis was associated with decreasing DNA synthesis as evaluated by BrdU incorporation assay, and abrogating endothelial cell ERK1/2 and Akt protein phosphorylation, the major signaling pathways involved in cellular processes of angiogenesis. In addition, KS-5 also inhibited bFGF-induced phosphorylation of mTOR and the major downstream effectors, eIF4E and p70S6K. Moreover, bFGF-induced protein synthesis was also inhibited by KS-5. Most importantly, KS-5 treatment in nude mice inhibited in vivo angiogenesis as revealed by Matrigel implant assay. In conclusion, the present study suggests that KS-5 has potential anti-angiogenetic effect for cancer therapy and other angiogenesis-dependent diseases. ? 2007 Elsevier Ireland Ltd. All rights reserved.
Subjects
Acridone derivatives; Angiogenesis; Endothelial cells
SDGs
Other Subjects
1,7 dihydroxy 3 methoxyacridone; acridone derivative; basic fibroblast growth factor; broxuridine; initiation factor 4E; ks 5; lactate dehydrogenase; mammalian target of rapamycin inhibitor; matrigel; mitogen activated protein kinase; protein kinase B; S6 kinase; unclassified drug; angiogenesis; animal experiment; animal model; animal tissue; antiangiogenic activity; article; cancer cell culture; cancer inhibition; cell proliferation; concentration response; controlled study; DNA synthesis; drug cytotoxicity; drug implantation; endothelium cell; enzyme phosphorylation; human; human cell; in vitro study; in vivo study; mouse; nonhuman; nude mouse; priority journal; protein synthesis; statistical analysis; Western blotting; Acridones; Angiogenesis Inhibitors; Blotting, Western; Cell Proliferation; Cells, Cultured; DNA Replication; Endothelium, Vascular; Fibroblast Growth Factor 2; Humans; Neovascularization, Physiologic; Protein Kinases; Mus musculus
Type
journal article