The farnesyltransferase inhibitor LB42708 suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting ras-dependent mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signal pathways.
Farnesyltransferase (FTase) inhibitors induce growth arrest and apoptosis in various human cancer cells by inhibiting the post-translational activation of Ras. FTase inhibitors also function to suppress the release of vascular endothelial growth factor (VEGF) from tumor cells by inhibiting Ras activation; however, the effects of FTase inhibitors on VEGF-induced angiogenesis in endothelial cells have not been studied. We have investigated the antiangiogenic effect and molecular mechanism of 4-((1-((1-((4-bromophenyl)methyl)-1H-imidazol-5-yl)methyl)-4-(1-napthalenyl)-1H-pyrrol-3-yl)carbonyl)-(9C1)-morpholine (LB42708), a selective nonpeptidic FTase inhibitor, using in vitro and in vivo assay systems. LB42708 inhibited VEGF-induced Ras activation and subsequently suppressed angiogenesis in vitro and in vivo by blocking the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase/p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric-oxide synthase pathways in endothelial cells without altering FAK/Src activation. In addition, this inhibitor suppressed VEGF-induced endothelial cell cycle progression at the G(1) phase by suppressing cyclin D1 expression and retinoblastoma phosphorylation as well as up-regulating the cyclin-dependent kinase inhibitors p21 and p27. Knockdown of Ras by short interfering RNA revealed similar inhibitory effects on VEGF-induced angiogenic signal events compared with LB42708. Moreover, the inhibitory effects of LB42708 were significantly higher than those of 4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide (SCH66336), a well known FTase inhibitor. LB42708 suppressed tumor growth and tumor angiogenesis in both xenograft tumor models of Ras-mutated HCT116 cells and its wild-type Caco-2 cells, indicating its potential application in the treatment of both Ras-mutated and wild type tumors. These data indicate that the antitumor effect of LB42708 can be associated with direct inhibition of VEGF-induced tumor angiogenesis by blocking Ras-dependent MAPK and PI3K/Akt signal pathways in tumor-associated endothelial cells.
Kim
Chun-Ki
CK
Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Kangwon-do 200-701, South Korea.
Choi
Yoon Kyung
YK
Lee
Hansoo
H
Ha
Kwon-Soo
KS
Won
Moo-Ho
MH
Kwon
Young-Guen
YG
Kim
Young-Myeong
YM
D001483:Base Sequence; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011758:Pyrroles / Q000494:pharmacology*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D018631:ras Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D007093:Imidazoles; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011758:Pyrroles; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D018631:ras Proteins; C514652:LB42708