HET0016 is a highly selective inhibitor of 20-hydroxy eicosatrienoic acid (20-HETE) synthase. The IC50 values for the catalytic synthesis of 20-HETE by recombinant CYP4A1, CYP4A2, and CYP4A3 are 17.7nM, 12.1nM, and 20.6nM, respectively [1-2]. 20-HETE is an effective vasoconstrictor that can inhibit Na+ transport in the proximal tubule and thick ascending limb of the loop of Henle (TALH) [3]. HET0016 can be used to inhibit angiogenesis and tumor growth [4].
In vitro, treatment with HET0016 (100μM; 24, 48h) significantly reduced the motility of 4T1 and MDA-MB-231 cells, the total area of cell invasion decreased, and cell migration also showed a similar reduction [4]. Treatment with HET0016 (1, 10μM; 48h) dose-dependently inhibited the cell proliferation of the 9L gliosarcoma cell line. HET0016 could inhibit proliferation induced by epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) and reduce the phosphorylation of PDGF receptors [5].
In vivo, HET0016 (10mg/kg/day; 5d; i.p.) Treatment reduced tumor growth in breast cancer xenograft model mice, and decreased tumor volume in both the early treatment group and the delayed treatment group [6]. HET0016 (10mg/kg/day; once every 12 hours for three days; i.p.) treatment significantly reduced the brain lesion volume and neurological deficits in collagenase-induced Intracerebral Hemorrhage (ICH) model mice, and decreased neuronal death, ROS production, gelatin dissolution activity and inflammatory response 3 days after ICH [7].
References:
[1] Seki T, et al. Cytochrome P450 4A isoform inhibitory profile of N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016), a selective inhibitor of 20-HETE synthesis. Biol Pharm Bull. 2005 Sep;28(9):1651-4.
[2] Borin T F, Zuccari D A P C, Jardim-Perassi B V, et al. HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice[J]. PLoS One, 2014, 9(12): e116247.
[3] Hoagland K M, Flasch A K, Roman R J. Inhibitors of 20-HETE formation promote salt-sensitive hypertension in rats[J]. Hypertension, 2003, 42(4): 669-673.
[4] Borin TF, et al. HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model. PLoS One. 2017 Jun 13;12(6): e0178830.
[5] Guo M, Roman R J, Fenstermacher J D, et al. 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[J]. The Journal of pharmacology and experimental therapeutics, 2006, 317(1): 97-108.
[6] Borin T F, Zuccari D A P C, Jardim-Perassi B V, et al. HET0016, a selective inhibitor of 20-HETE synthesis, decreases pro-angiogenic factors and inhibits growth of triple negative breast cancer in mice[J]. PLoS One, 2014, 9(12): e116247.
[7] Han X, Zhao X, Lan X, et al. 20-HETE synthesis inhibition promotes cerebral protection after intracerebral hemorrhage without inhibiting angiogenesis. J Cereb Blood Flow Metab. 2019;39(8):1531-1543.
HET0016 是一种高选择性的20-羟基花生四烯酸（20-HETE）合成酶抑制剂，对重组CYP4A1、CYP4A2和CYP4A3催化20-HETE合成作用的IC50值分别为17.7nM, 12.1nM和20.6nM [1-2]。20-HETE是一种有效的血管收缩剂，能够抑制近端小管和亨利氏袢升支粗管(TALH)中的Na+转运[3]。HET0016可用于抑制血管生成和肿瘤生长 [4]。
在体外，HET0016（100μM; 24,48h）处理显著降低了4T1和MDA-MB-231细胞的运动性，细胞侵袭的总面积减少，细胞迁移也显示出类似的降低 [4]。HET0016（1,10μM; 48h）处理剂量依赖性地抑制了9L胶质肉瘤细胞系的细胞增殖。HET0016能够抑制表皮生长因子（EGF）和血小板衍生生长因子（PDGF）诱导的增殖并减少PDGF受体的磷酸化 [5]。
在体内，HET0016（10mg/kg/day; 5d; i.p.）治疗减少了乳腺癌异种移植模型小鼠的肿瘤生长，在早期治疗组和延迟治疗组中均降低了肿瘤体积 [6]。HET0016（10mg/kg/day; 每12h一次, 持续三天; i.p.）治疗显著减少了胶原酶诱导的脑出血（ICH）模型小鼠脑病变体积和神经功能缺损，并减少了ICH后3天的神经元死亡、ROS 产生、明胶溶解活性和炎症反应 [7]。