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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Human U251 Glioma Cell Proliferation Is Suppressed by HET0016 [N-Hydroxy-N'-(4-butyl-2-methylphenyl)formamidine], a Selective Inhibitor of CYP4A

Eye Care Services, Henry Ford Hospital, Detroit, Michigan (M.G., P.A.E.); Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin (R.J.R.); Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Eye Care Services, Henry Ford Hospital, and Department of Anesthesiology, Wayne State University, Detroit, Michigan (A.G.S.)

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 T₀ (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 G₀/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.

Address correspondence to: Dr. Meng Guo, Eye Care Services, Henry Ford Hospital, One Ford Place, 4D, Detroit, MI 48202-3450. E-mail: mguo1{at}hfhs.org

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