Abstract
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 G1 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.
Footnotes
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.063586.
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This work was supported by the Korean Ministry of Education, Science, and Technology (Regional Core Research Program/Medical and Bio-Materials Research Center); and the National Research Laboratory [Grant 20090083119].
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ABBREVIATIONS:
- VEGF
- vascular endothelial growth factor
- FTase
- farnesyltransferase
- ERK
- extracellular signal-regulated protein kinase
- MAPK
- mitogen-activated protein kinase
- MEK
- mitogen-activated protein kinase kinase
- FAK
- focal adhesion kinase
- PI3K
- phosphatidylinositol 3-kinase
- eNOS
- endothelial nitric-oxide synthase
- NOx
- nitrite plus nitrate
- HUVEC
- human umbilical vein endothelial cell
- Rb
- retinoblastoma protein
- CAM
- chick chorioallantoic membrane
- FITC
- fluorescein isothiocyanate
- CDK
- cyclin-dependent kinase
- GGTase I
- geranylgeranyltransferase I
- siRNA
- short interfering RNA
- FBS
- fetal bovine serum
- PBS
- phosphate-buffered saline
- SCH66336
- 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
- LB42708
- 4-((1-((1-((4-bromophenyl)methyl)-1H-imidazol-5-yl)methyl)-4-(1-napthalenyl)-1H-pyrrol-3-yl)carbonyl)-(9C1)-morpholine.
- Received January 13, 2010.
- Accepted April 19, 2010.
- Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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