Antiangiogenic effect of inhibitors of cytochrome P450 on rats with glioblastoma multiforme. J Cereb Blood Flow Metab 2008 Aug;28(8):1431-9
Date
04/17/2008Pubmed ID
18414496Pubmed Central ID
PMC2637201DOI
10.1038/jcbfm.2008.31Scopus ID
2-s2.0-48749116836 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
Cytochrome P450 epoxygenase catalyzes 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) from arachidonic acid (AA). In 1996, our group identified the expression of the cytochrome P450 2C11 epoxygenase (CYP epoxygenase) gene in astrocytes. Because of our finding an array of physiological functions have been attributed to EETs in the brain, one of the actions of EETs involves a predominant role in brain angiogenesis. Blockade of EETs formation with different epoxygenase inhibitors decreases endothelial tube formation in cocultures of astrocytes and capillary endothelial cells. The intent of this investigation was to determine if pharmacologic inhibition of formation of EETs is effective in reducing capillary formation in glioblastoma multiforme with a concomitant reduction in tumor volume and increase in animal survival time. Two mechanistically different inhibitors of CYP epoxygenase, 17-octadecynoic acid (17-ODYA) and miconazole, significantly reduced capillary formation and tumor size in glial tumors formed by injection of rat glioma 2 (RG2) cells, also resulting in an increased animal survival time. However, we observed that 17-ODYA and miconazole did not inhibit the formation of EETs in tumor tissue. This implies that 17-ODYA and miconazole appear to exert their antitumorogenic function by a different mechanism that needs to be explored.
Author List
Zagorac D, Jakovcevic D, Gebremedhin D, Harder DRMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAnimals
Antifungal Agents
Antineoplastic Agents
Arachidonic Acid
Aryl Hydrocarbon Hydroxylases
Astrocytes
Cytochrome P450 Family 2
Enzyme Inhibitors
Fatty Acids, Unsaturated
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Glioblastoma
Male
Miconazole
Neoplasm Proteins
Neovascularization, Pathologic
Rats
Rats, Inbred F344
Steroid 16-alpha-Hydroxylase
