Human U251 glioma cell proliferation is suppressed by HET0016 [N-hydroxy-N′-(4-butyl-2-methylphenyl)formamidine], a selective inhibitor of CYP4A

Meng Guo, Richard J. Roman, J R Falck, Paul A. Edwards, A. Guillermo Scicli

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Abstract

We have previously reported that HET0016 [N-hydroxy-N′-(4-butyl-2 methylphenyl)formamidine], a selective inhibitor of CYP4A and thus 20-HETE (20-hydroxyeicosatetraenoic acid) synthesis, inhibits endothelial cell proliferation and decreases angiogenesis induced by human glioma cell U251. A stable 20-HETE agonist, WIT003 [20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (1 μM)], increased U251 cell proliferation from 3.9- to 4.8-folds from T 0 (time of the treatment). We examined the effects of HET0016 on the growth of U251. HET0016 inhibited U251 basal cell proliferation in a dose-dependent manner. 10 μM HET0016 suppressed 56% of U251 proliferation and significantly increased the proportions of the cells arrested in the G 0/G1 phase of the cell cycle. Exposure to HET0016 (as early as 4 h) reduced protein tyrosine and p42/p44 MAPK (mitogen-activated protein kinase) phosphorylation. Furthermore, HET0016 significantly inhibited the U251 proliferation and phosphorylation of both the epidermal growth factor (EGF) receptor and p42/p44 MAPK induced by EGF. CYP4A mRNA and proteins were both present in U251. This suggests that HET0016 inhibited U251 proliferation by inhibiting 20-HETE synthesis. However, U251 did not synthesize 20-HETE in the presence of arachidonic acid. This implies that HET0016 suppresses U251 proliferation by mechanisms that are not yet clear but may involve activities other than inhibition of 20-HETE synthesis. We concluded that HET0016 may be the prototype of novel compounds that suppress human glioma cell proliferation.

Original languageEnglish (US)
Pages (from-to)526-533
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume315
Issue number2
DOIs
StatePublished - Nov 2005

Fingerprint

Cytochrome P-450 CYP4A
Glioma
Cell Proliferation
Mitogen-Activated Protein Kinase 1
Phosphorylation
G1 Phase
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Arachidonic Acid
Tyrosine
Cell Cycle
Proteins
Endothelial Cells
N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Messenger RNA
Growth

ASJC Scopus subject areas

  • Pharmacology

Cite this

Human U251 glioma cell proliferation is suppressed by HET0016 [N-hydroxy-N′-(4-butyl-2-methylphenyl)formamidine], a selective inhibitor of CYP4A. / Guo, Meng; Roman, Richard J.; Falck, J R; Edwards, Paul A.; Scicli, A. Guillermo.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 315, No. 2, 11.2005, p. 526-533.

Research output: Contribution to journalArticle

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abstract = "We have previously reported that HET0016 [N-hydroxy-N′-(4-butyl-2 methylphenyl)formamidine], a selective inhibitor of CYP4A and thus 20-HETE (20-hydroxyeicosatetraenoic acid) synthesis, inhibits endothelial cell proliferation and decreases angiogenesis induced by human glioma cell U251. A stable 20-HETE agonist, WIT003 [20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (1 μM)], increased U251 cell proliferation from 3.9- to 4.8-folds from T 0 (time of the treatment). We examined the effects of HET0016 on the growth of U251. HET0016 inhibited U251 basal cell proliferation in a dose-dependent manner. 10 μM HET0016 suppressed 56{\%} of U251 proliferation and significantly increased the proportions of the cells arrested in the G 0/G1 phase of the cell cycle. Exposure to HET0016 (as early as 4 h) reduced protein tyrosine and p42/p44 MAPK (mitogen-activated protein kinase) phosphorylation. Furthermore, HET0016 significantly inhibited the U251 proliferation and phosphorylation of both the epidermal growth factor (EGF) receptor and p42/p44 MAPK induced by EGF. CYP4A mRNA and proteins were both present in U251. This suggests that HET0016 inhibited U251 proliferation by inhibiting 20-HETE synthesis. However, U251 did not synthesize 20-HETE in the presence of arachidonic acid. This implies that HET0016 suppresses U251 proliferation by mechanisms that are not yet clear but may involve activities other than inhibition of 20-HETE synthesis. We concluded that HET0016 may be the prototype of novel compounds that suppress human glioma cell proliferation.",
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