Imatinib Mesylate (STI571) is an orally bioavailable multi-target inhibitor with IC50 values for Bcr-Abl, c-Kit and PDGFR are 0.6μM, 0.1μM and 0.1μM respectively [1]. Tyrosine kinase Bcr-Abl is present throughout the entire disease process of almost all cases of chronic myeloid leukemia (CML) [2]. Imatinib Mesylate is used to treat chronic myeloid leukemia and gastrointestinal stromal tumors [3].
In vitro, Imatinib Mesylate (10μM) incubated with T cells for 1h, reduced the phosphorylation of Lck, ERK 1/2 and Rb proteins, and decreased the levels of cyclin D3 and activated nuclear transcription factor κB (NF-κB) [4]. Different concentrations of Imatinib Mesylate (10, 100, 1000 and 10000ng/mL) were combined with PRI-2191 to treat human lung adenocarcinoma A549 cells for 96 hours. By comparing the proliferation curves of each group of cells, it was observed that the inhibition of cell proliferation exhibited a cumulative effect, and the two had a synergistic effect [5].
In vivo, Imatinib Mesylate (50mg/kg/day; i.p.) was administered 20 minutes before ischemia modeling in rats with ischemia/reperfusion injury (IRI), significantly increasing the level of interleukin (IL)-10, maintaining the expression of vascular endothelial cells (VEC) stable, and inhibiting pCrkL [6]. Imatinib Mesylate (75mg/kg/day; 19 days; i.p.) combined with the vitamin D3 analog PRI-2191 downregulated the expression of VEGF in the tumor tissues of mice, upregulated p53 and downregulated Bcl-2, and significantly inhibited tumor growth [5].
References:
[1] Buchdunger E, Zimmermann J, Mett H, et al. Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class [retracted in: Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):12069.
[2] Druker B J, Sawyers C L, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome[J]. New England Journal of Medicine, 2001, 344(14): 1038-1042.
[3] Tibullo D, Giallongo C, La Cava P, et al. Effects of imatinib mesylate in osteoblastogenesis[J]. Experimental hematology, 2009, 37(4): 461-468.
[4] Dietz A B, Souan L, Knutson G J, et al. Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo[J]. Blood, 2004, 104(4): 1094-1099.
[5] Maj E, Filip-Psurska B, Świtalska M, Kutner A, Wietrzyk J. Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model. Int J Mol Sci. 2015 Nov 13;16(11):27191-207.
[6] Tanaka S, Chen-Yoshikawa TF, Kajiwara M, Menju T, Ohata K, Takahashi M, Kondo T, Hijiya K, Motoyama H, Aoyama A, Masuda S, Date H. Protective Effects of Imatinib on Ischemia/Reperfusion Injury in Rat Lung. Ann Thorac Surg. 2016 Nov;102(5):1717-1724.
Imatinib Mesylate (STI571)是一种口服生物有效的多靶点抑制剂，对Bcr-Abl，c-Kit和PDGFR的IC50分别为0.6μM，0.1μM 和0.1μM [1]。酪氨酸激酶Bcr-Abl存在于几乎所有慢性髓细胞白血病（CML）的整个疾病过程中 [2]。Imatinib Mesylate用于治疗慢性粒细胞白血病和胃肠道间质瘤 [3]。
在体外，Imatinib Mesylate（10μM）处理T细胞1小时，可减少Lck、ERK 1/2和Rb蛋白的磷酸化，并降低细胞周期蛋白D3的水平和活化的核转录因子κB（NF-κB）的含量 [4]。不同浓度的Imatinib Mesylate（10、100、1000和10000ng/mL）与PRI-2191联合使用处理人肺腺癌A549细胞96小时，比较各组细胞的增殖曲线，细胞增殖抑制呈现出累积效应，且两者具有协同作用 [5]。
在体内，Imatinib Mesylate（50mg/kg/d；i.p.）在对缺血/再灌注损伤（IRI）的大鼠进行缺血模型构建前20分钟给予，显著提高了白细胞介素（IL）-10的水平，维持了血管内皮细胞（VEC）的表达稳定，并抑制了pCrkL的活性 [6]。Imatinib Mesylate（75mg/kg/d；i.p.）与维生素D3类似物PRI-2191联合使用持续19天，下调了小鼠肿瘤组织中的VEGF表达，上调了p53，下调了 Bcl-2的表达，并显著抑制了肿瘤生长[5]。