TY - JOUR
T1 - Human U251 glioma cell proliferation is suppressed by HET0016 [N-hydroxy-N′-(4-butyl-2-methylphenyl)formamidine], a selective inhibitor of CYP4A
AU - Guo, Meng
AU - Roman, Richard J.
AU - Falck, J R
AU - Edwards, Paul A.
AU - Scicli, A. Guillermo
PY - 2005/11
Y1 - 2005/11
N2 - 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.
AB - 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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U2 - 10.1124/jpet.105.088567
DO - 10.1124/jpet.105.088567
M3 - Article
C2 - 16081682
AN - SCOPUS:27144552930
SN - 0022-3565
VL - 315
SP - 526
EP - 533
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -