Human U251 glioma cell proliferation is suppressed by HET0016 [N-hydroxy-N′-(4-butyl-2-methylphenyl)formamidine], a selective inhibitor of CYP4A
Human U251 glioma cell proliferation is suppressed by HET0016 [N-hydroxy-N′-(4-butyl-2-methylphenyl)formamidine], a selective inhibitor of CYP4A
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DOI：
10.1124/jpet.105.088567
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发表时间：
2005-11-01
影响因子：
3.5
通讯作者：
Scicli, AG
中科院分区：
文献类型：
--
作者：
Guo, M;Roman, RJ;Scicli, AG
我们以前曾报道，HET 0016 [N-羟基-N '-（4-丁基-2-甲基苯基）甲脒]，一种CYP 4A和20-HETE（20-hydroxyyeicosatetraenoic acid）合成的选择性抑制剂，可抑制人胶质瘤细胞U251诱导的内皮细胞增殖和血管生成。稳定的20-HETE激动剂WIT 003 [20-hydroxyyeicosa-5（Z），14（Z）-dienoic acid（1 μ M）]使U251细胞增殖从T0（处理时间）的3.9倍增加到4.8倍。我们检查了HET 0016对U251生长的影响。HET 0016以剂量依赖性方式抑制U251基底细胞增殖。10 μ M的HET 0016抑制了56%的U251增殖，并显著增加了停滞在细胞周期G（o）/G（1）期的细胞比例。暴露于HET 0016（早在4 h）可降低蛋白酪氨酸和p42/p44 MAPK（丝裂原活化蛋白激酶）磷酸化。此外，HET 0016显著抑制U251增殖和EGF诱导的表皮生长因子（EGF）受体和p42/p44 MAPK的磷酸化。U251中存在CYP 4A mRNA和蛋白。这表明HET 0016通过抑制20-HETE合成来抑制U251增殖。然而，U251在花生四烯酸存在下不合成20-HETE。这意味着HET 0016通过尚不清楚的机制抑制U251增殖，但可能涉及抑制20-HETE合成以外的活性。我们的结论是，HET 0016可能是抑制人脑胶质瘤细胞增殖的新型化合物的原型。
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 mu M)], 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 mu M HET0016 suppressed 56% of U251 proliferation and significantly increased the proportions of the cells arrested in the G(o)/G(1) phase of the cell cycle. Exposure to HET0016 (as early as 4 h) reduced protein tyrosine and p42/p44 MAPK (mitogenactivated 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.