ES 936 is a potent and specific NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitor[1-2]. ES 936 exhibits superoxide-scavenging activity and the ability to regulate cancer progression[3-4].
In vitro, treatment of renal cell carcinoma Caki cells with ES 936 (100nM) for 12 hours, ES 936 significantly inhibits the enzymatic activity of NAD(P)H:quinone oxidoreductase 1 (NQO1)[5]. Treatment of low-density cultured human adenocarcinoma HeLa cells with ES 936 (100nM–1μM) for 24 hours, ES 936 significantly stimulates DNA synthesis and cell growth[6]. ES 936 (100nM) pretreatment of TrHBMEC (transformed human bone marrow endothelial cells) for 2 hours, followed by stimulation with TNFα (10ng/ml) for 2-6 hours, ES 936 significantly inhibited the mRNA and protein expression of adhesion molecules such as E-selectin, VCAM-1, and ICAM-1, while also reducing the adhesive function of CD34⁺ hematopoietic cells (KG1a)[7]. ES 936 (500nM) treatment of BxPc-3 human pancreatic cancer cells for 2 hours did not affect the binding of NQO1 to the mitotic spindle, indicating that the association of NQO1 with the spindle is independent of its catalytic activity state[8].
In vivo, daily intraperitoneal injection of ES 936 (5mg/kg) for 10 consecutive days in female athymic nude mice bearing MIA PaCa-2 human pancreatic cancer xenografts, ES 936 significantly inhibits the tumor growth rate[7].
References:
[1] Okubo A, Yasuhira S, Shibazaki M, et al. NAD(P)H dehydrogenase, quinone 1 (NQO1), protects melanin-producing cells from cytotoxicity of rhododendrol. Pigment Cell Melanoma Res. 2016 May;29(3):309-16.
[2] Winski SL, Faig M, Bianchet MA, et al. Characterization of a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1 by biochemical, X-ray crystallographic, and mass spectrometric approaches. Biochemistry. 2001 Dec 18;40(50):15135-42.
[3] Dehn DL, Siegel D, Swann E, et al. Biochemical, cytotoxic, and genotoxic effects of ES936, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, in cellular systems. Mol Pharmacol. 2003 Sep;64(3):714-20.
[4] Reigan P, Colucci MA, Siegel D, et al. Development of indolequinone mechanism-based inhibitors of NAD(P)H:quinone oxidoreductase 1 (NQO1): NQO1 inhibition and growth inhibitory activity in human pancreatic MIA PaCa-2 cancer cells. Biochemistry. 2007 May 22;46(20):5941-50.
[5] Park EJ, Min KJ, Choi KS, et al. Dicoumarol sensitizes renal cell carcinoma Caki cells to TRAIL-induced apoptosis through down-regulation of Bcl-2, Mcl-1 and c-FLIP in a NQO1-independent manner. Exp Cell Res. 2014 Apr 15;323(1):144-154.
[6] González-Aragón D, Alcaín FJ, Ariza J, et al. ES936 stimulates DNA synthesis in HeLa cells independently on NAD(P)H:quinone oxidoreductase 1 inhibition, through a mechanism involving p38 MAPK. Chem Biol Interact. 2010 Jul 30;186(2):174-83.
[7] Zhou H, Dehn D, Kepa JK, et al. NAD(P)H:quinone oxidoreductase 1-compromised human bone marrow endothelial cells exhibit decreased adhesion molecule expression and CD34+ hematopoietic cell adhesion. J Pharmacol Exp Ther. 2010 Jul;334(1):260-8.
[8] Siegel D, Kepa JK, Ross D. NAD(P)H:quinone oxidoreductase 1 (NQO1) localizes to the mitotic spindle in human cells. PLoS One. 2012;7(9):e44861.
[9] Dehn DL, Siegel D, Zafar KS, et al. 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo. Mol Cancer Ther. 2006 Jul;5(7):1702-9.
ES 936一种有效的特异性NAD(P)H:醌氧化还原酶1（NQO1）抑制剂[1-2]。ES 936具有超氧化物清除活性及调控癌症发展活性[3-4]。
在体外，ES 936（100nM）处理肾细胞癌Caki细胞12小时，显著抑制NAD(P)H:醌氧化还原酶1（NQO1）的酶活性[5]。ES 936（100nM–1μM）处理低密度培养的人腺癌HeLa细胞24小时，显著刺激DNA合成和细胞生长[6]。ES 936（100nM）预处理TrHBMEC（转化人骨髓内皮细胞）2小时，随后以TNFα（10ng/ml）刺激2-6小时，显著抑制E-selectin、VCAM-1和ICAM-1等黏附分子的mRNA及蛋白表达，同时降低CD34+造血细胞（KG1a）的黏附功能[7]。ES 936（500nM）处理BxPc-3人胰腺癌细胞2小时，ES 936处理不影响NQO1与有丝分裂纺锤体的结合，表明NQO1与纺锤体的结合不依赖于其催化活性状态[8]。
在体内，ES 936（5mg/kg）每日腹腔注射一次，连续10天处理携带MIA PaCa-2人胰腺癌异种移植瘤的雌性无胸腺裸鼠，显著抑制肿瘤生长速率[8]。