W-7 hydrochloride is a potent calmodulin antagonist that inhibits the Ca2+-calmodulin-induced activation of myosin light chain kinase with an IC50 value of 25μM [1]. W-7 hydrochloride enhances thromboxane A2 receptor-mediated signal transduction at the receptor/G protein coupling, leading to the enhancement of phosphoinositide hydrolysis and Ca2+ mobilization [2]. W-7 hydrochloride induces apoptosis and blocks the Akt activation[3]. W-7 hydrochloride has been widely used to inhibit peak currents of heterologously expressed Kv4.3 channels in Xenopus oocytes[4].
In vitro, W-7 hydrochloride treatment for 1h reduced colony formation of MDA-MB-231 cells with an IC50 value of 53μM[5]. Treatment with 25μM W-7 hydrochloride for 48 hours significantly inhibited the replication of Dengue virus in Huh-7 cells, reducing the secretion of NS1 protein and the expression of NS3 protein[6]. Treatment with 0.5μM W-7 hydrochloride for 24 hours significantly inhibited cytochrome c release, caspase-3 activation, reactive oxygen species (ROS) production, and cell death in PC12 cells induced by rotenone[7]. Treatment with 20μM W-7 hydrochloride for 150 minutes significantly inhibited secretion of de novo synthesized glycerolipids from McArdle RH-7777 cells[8]. Treatment with 40μM W-7 hydrochloride for 24 hours down-regulated cyclins and up-regulated p21cip1 in RPMI 8226 cells, induced cell apoptosis, accompanied by an increase in intracellular calcium ion levels and depolarization of mitochondrial membrane potential, as well as a decrease in STAT3 phosphorylation level and the reduction in Mcl-1 protein expression[9].
In vivo, W-7 hydrochloride treatment via intraperitoneal injection at a dose of 3mg/kg (5 days per week) for 18 days reduced tumor growth in RPMI 8226 cell-xenograft mouse models[9].
References:
[1] Asano M. Divergent pharmacological effects of three calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), chlorpromazine and calmidazolium, on isometric tension development and myosin light chain phosphorylation in intact bovine tracheal smooth muscle[J]. The Journal of pharmacology and experimental therapeutics, 1989, 251(2): 764-773.
[2] Ohkubo S, Nakahata N, Ohizumi Y. ML-7 and W-7 facilitate thromboxane A2-mediated Ca2+ mobilization in rabbit platelets[J]. European journal of pharmacology, 1996, 298(2): 175-183.
[3] Deb T B, Coticchia C M, Dickson R B. Calmodulin-mediated activation of Akt regulates survival of c-Myc-overexpressing mouse mammary carcinoma cells[J]. Journal of Biological Chemistry, 2004, 279(37): 38903-38911.
[4] Qu Y J, Bondarenko V E, Xie C, et al. W-7 modulates Kv4. 3: pore block and Ca2+-calmodulin inhibition[J]. American Journal of Physiology-Heart and Circulatory Physiology, 2007, 292(5): H2364-H2377.
[5] Wei J W, Hickie R A, Klaassen D J. Inhibition of human breast cancer colony formation by anticalmodulin agents: trifluoperazine, W-7, and W-13[J]. Cancer chemotherapy and pharmacology, 1983, 11(2): 86-90.
[6] Bautista-Carbajal P, Soto-Acosta R, Angel-Ambrocio A H, et al. The calmodulin antagonist W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride) inhibits DENV infection in Huh-7 cells[J]. Virology, 2017, 501: 188-198.
[7] Lee C S, Park S Y, Ko H H, et al. Inhibition of MPP+-induced mitochondrial damage and cell death by trifluoperazine and W-7 in PC12 cells[J]. Neurochemistry international, 2005, 46(2): 169-178.
[8] Rasouli M, Trischuk T C, Lehner R. Calmodulin antagonist W-7 inhibits de novo synthesis of cholesterol and suppresses secretion of de novo synthesized and preformed lipids from cultured hepatocytes[J]. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 2004, 1682(1-3): 92-101.
[9] Yokokura S, Yurimoto S, Matsuoka A, et al. Calmodulin antagonists induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in vivo in human multiple myeloma[J]. BMC cancer, 2014, 14(1): 882.
W-7 hydrochloride是一种强效的钙调蛋白拮抗剂，可抑制钙离子-钙调蛋白诱导的肌球蛋白轻链激酶激活，IC50值为25μM[1]。W-7 hydrochloride在受体/G蛋白偶联水平增强血栓素A2受体介导的信号转导，从而增强磷酸肌醇水解和钙离子动员[2]。W-7 hydrochloride诱导细胞凋亡，阻断Akt活化[3]。W-7 hydrochloride已被广泛用于抑制异源表达于非洲爪蟾卵母细胞中的Kv4.3通道的峰值电流[4]。
在体外，W-7 hydrochloride处理1小时降低了MDA-MB-231细胞的克隆形成能力，IC50值为53μM[5]。使用25μM的W-7 hydrochloride处理48小时，显著抑制了Dengue病毒在Huh-7细胞中的复制，降低了NS1蛋白的分泌和NS3蛋白的表达[6]。使用0.5μM的W-7 hydrochloride处理24小时，显著抑制了鱼藤酮诱导的PC12细胞中细胞色素c的释放、caspase-3的激活、活性氧（ROS）的产生以及细胞死亡[7]。使用20μM的W-7 hydrochloride处理150分钟，显著抑制了McArdle RH-7777细胞中新合成的甘油脂的分泌[8]。40μM的W-7 hydrochloride处理24小时可下调RPMI 8226细胞中的细胞周期蛋白和上调 p21cip1，诱导细胞凋亡，伴随着细胞内钙离子水平升高和线粒体膜电位去极化，以及 STAT3 磷酸化水平下降和Mcl-1蛋白表达降低[9]。
在体内，通过腹腔注射给予W-7 hydrochloride，剂量为3mg/kg（每周5天），持续18天，可抑制RPMI 8226细胞异种移植小鼠模型中的肿瘤生长[9]。