9L gliosarcoma cell proliferation and tumor growth in rats are suppressed by N-hydroxy-N′-(4-butyl-2-methylphenol) formamidine (HET0016), a selective inhibitor of CYP4A

Meng Guo, Richard J. Roman, Joseph D. Fenstermacher, Stephen L. Brown, John R. Falck, Ali Syed Arbab, Paul A. Edwards, A. Guillermo Scicli

Research output: Contribution to journalArticle

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Abstract

The present study examined the effects of N-hydroxy-N′-(4-butyl-2 methylphenyl) formamidine (HET0016), a selective inhibitor of the formation of 20-hydroxyeicosatrienoic acid (20-HETE) on the growth of 9L rat gliosarcoma cells in vitro and in vivo. After 48 h of incubation, HET0016 reduced the proliferation of 9L in vitro by 55%, and this was associated with a fall in p42/p44 mitogen-activated protein kinase and stress-activated protein kinase/c-Jun NH2-terminal kinase phosphorylation and increased apoptosis. HET0016 inhibited epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)-induced proliferation and diminished phosphorylation of PDGF receptors. A stable 20-HETE analog increased 9L cell proliferation. In vivo, chronic administration of HET0016 (10 mg/kg/day i.p.) for 2 weeks reduced the volume of 9L tumors by 80%. This was accompanied by a 4-fold reduction in the mitotic index, a 3- to 4-fold increase in the apoptotic index, and a ∼50% decrease in vascularization in the tumor. HET0016 treatment increased mean survival time of the animals from 17 to 22 days. Liquid chromatography/mass spectrometry experiments indicated that neither 9L cells grown in vitro nor 9L tumors removed produce 20-HETE when incubated with arachidonic acid. The normal surrounding brain tissue, however, avidly makes 20-HETE, and this activity is selectively inhibited by HET0016. These results suggest that HET0016 may be the prototype of a class of antigrowth compounds that may be efficacious for treating malignant brain tumors. In vivo, it may act in part by inhibiting the formation of 20-HETE by the surrounding tissue. However, the antiproliferative effects of HET0016 on 9L cells in vitro seem unrelated to its ability to inhibit the formation of 20-HETE.

Original languageEnglish (US)
Pages (from-to)97-108
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume317
Issue number1
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

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Cytochrome P-450 CYP4A
Gliosarcoma
Cell Proliferation
Acids
Growth
Neoplasms
Phosphorylation
Platelet-Derived Growth Factor Receptors
Mitotic Index
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 1
Platelet-Derived Growth Factor
Heat-Shock Proteins
Tumor Burden
Epidermal Growth Factor
Arachidonic Acid
Brain Neoplasms
Liquid Chromatography
Protein Kinases
2-cresol

ASJC Scopus subject areas

  • Pharmacology

Cite this

9L gliosarcoma cell proliferation and tumor growth in rats are suppressed by N-hydroxy-N′-(4-butyl-2-methylphenol) formamidine (HET0016), a selective inhibitor of CYP4A. / Guo, Meng; Roman, Richard J.; Fenstermacher, Joseph D.; Brown, Stephen L.; Falck, John R.; Arbab, Ali Syed; Edwards, Paul A.; Scicli, A. Guillermo.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 317, No. 1, 01.04.2006, p. 97-108.

Research output: Contribution to journalArticle

Guo, Meng ; Roman, Richard J. ; Fenstermacher, Joseph D. ; Brown, Stephen L. ; Falck, John R. ; Arbab, Ali Syed ; Edwards, Paul A. ; Scicli, A. Guillermo. / 9L gliosarcoma cell proliferation and tumor growth in rats are suppressed by N-hydroxy-N′-(4-butyl-2-methylphenol) formamidine (HET0016), a selective inhibitor of CYP4A. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 317, No. 1. pp. 97-108.
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abstract = "The present study examined the effects of N-hydroxy-N′-(4-butyl-2 methylphenyl) formamidine (HET0016), a selective inhibitor of the formation of 20-hydroxyeicosatrienoic acid (20-HETE) on the growth of 9L rat gliosarcoma cells in vitro and in vivo. After 48 h of incubation, HET0016 reduced the proliferation of 9L in vitro by 55{\%}, and this was associated with a fall in p42/p44 mitogen-activated protein kinase and stress-activated protein kinase/c-Jun NH2-terminal kinase phosphorylation and increased apoptosis. HET0016 inhibited epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)-induced proliferation and diminished phosphorylation of PDGF receptors. A stable 20-HETE analog increased 9L cell proliferation. In vivo, chronic administration of HET0016 (10 mg/kg/day i.p.) for 2 weeks reduced the volume of 9L tumors by 80{\%}. This was accompanied by a 4-fold reduction in the mitotic index, a 3- to 4-fold increase in the apoptotic index, and a ∼50{\%} decrease in vascularization in the tumor. HET0016 treatment increased mean survival time of the animals from 17 to 22 days. Liquid chromatography/mass spectrometry experiments indicated that neither 9L cells grown in vitro nor 9L tumors removed produce 20-HETE when incubated with arachidonic acid. The normal surrounding brain tissue, however, avidly makes 20-HETE, and this activity is selectively inhibited by HET0016. These results suggest that HET0016 may be the prototype of a class of antigrowth compounds that may be efficacious for treating malignant brain tumors. In vivo, it may act in part by inhibiting the formation of 20-HETE by the surrounding tissue. However, the antiproliferative effects of HET0016 on 9L cells in vitro seem unrelated to its ability to inhibit the formation of 20-HETE.",
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AU - Brown, Stephen L.

AU - Falck, John R.

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