Molecular mechanism of the inhibitory effect of KS-5 on bFGF-induced angiogenesis in vitro and in vivo.
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 p70(S6K). 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.
Peng
Chieh-Yu
CY
Pharmacological Institute, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei, Taiwan.
Pan
Shiow-Lin
SL
Lee
Kuo-Hsiung
KH
Bastow
Kenneth F
KF
Teng
Che-Ming
CM
D054831:Acridones / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D018919:Neovascularization, Physiologic; D011494:Protein Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
C529319:1,7-dihydroxy-3-methoxyacridone; D054831:Acridones; D020533:Angiogenesis Inhibitors; D016222:Fibroblast Growth Factor 2; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases