RT Journal Article
SR Electronic
T1 9L Gliosarcoma Cell Proliferation and Tumor Growth in Rats Are Suppressed by <em>N-</em>Hydroxy-<em>N</em>′-(4-butyl-2-methylphenol) Formamidine (HET0016), a Selective Inhibitor of CYP4A
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 97
OP 108
DO 10.1124/jpet.105.097782
VO 317
IS 1
A1 Meng Guo
A1 Richard J. Roman
A1 Joseph D. Fenstermacher
A1 Stephen L. Brown
A1 John R. Falck
A1 Ali S. Arbab
A1 Paul A. Edwards
A1 A. Guillermo Scicli
YR 2006
UL http://jpet.aspetjournals.org/content/317/1/97.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics