KCC009, a highly specific and irreversible inhibitor of transglutaminase 2 (TG2), can induce p53-independent radio-sensitization[1]. KCC009 can disrupt the adhesion plaque complex on the surface of glioblastoma cells, resulting in a decrease in cell migration ability, making the cells more sensitive to chemotherapy and leading to cell death[2]. KCC009 has been widely used to promote apoptosis of glioma and meningioma cells, and to enhance the chemosensitivity of cells[3].
In vitro, KCC009 pretreatment (250μM) for 1 hour can inhibit the production of cytokines in UV-irradiated keratinocytes and reduce the transcriptional activity of NF-κB[4]. Pretreatment of KCC009 (3.91μM; 24 hours) increased the expression of p21, Bax, p-caspase-3, and decreased expressions of Bcl-2 and Cyclin D in irradiated (6Gy) H1299/WT-p53 cells[5]. Treatment with 1mM KCC009 for 24 hours can induce apoptosis in U87 cells, accompanied by cell detachment from the cell culture plate and loss of cell membrane integrity[6].
In vivo, KCC009 treatment via intraperitoneal injection (20mg/kg; three times a day) for 6 days can alleviate the liver hypertrophy induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in mice[7]. Daily intraperitoneal injection of a 50mg/kg dose of KCC009 for 6 weeks prevented the increase in total calcium extraction in the aortic tissue of rats induced by warfarin [8].
References:
[1] Frese-Schaper M, Schardt J A, Sakai T, et al. Inhibition of tissue transglutaminase sensitizes TRAIL-resistant lung cancer cells through upregulation of death receptor 5[J]. FEBS letters, 2010, 584(13): 2867-2871.
[2] Yuan L, Behdad A, Holmes T, et al. Tissue transglutaminase 2 inhibitor, KCC009 results in disruption of focal adhesion complexes in glioblastoma cells with subsequent loss of cellular motility and sensitization to cell death[J]. Cancer Research, 2008, 68(9_Supplement): LB-193-LB-193.
[3] Yuan L, Behdad A, Siegel M, et al. Tissue transgluaminase 2 expression in meningiomas[J]. Journal of neuro-oncology, 2008, 90(2): 125-132.
[4] Lee S J, Lee K B, Son Y H, et al. Transglutaminase 2 mediates UV-induced skin inflammation by enhancing inflammatory cytokine production[J]. Cell death & disease, 2017, 8(10): e3148-e3148.
[5] Huayin S, Dong Y, Chihong Z, et al. Transglutaminase 2 inhibitor KCC009 induces p53-independent radiosensitization in lung adenocarcinoma cells[J]. Medical science monitor: international medical journal of experimental and clinical research, 2016, 22: 5041.
[6] Yuan L, Choi K, Khosla C, et al. Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas[J]. Molecular cancer therapeutics, 2005, 4(9): 1293-1302.
[7] Strnad P, Siegel M, Toivola D M, et al. Pharmacologic transglutaminase inhibition attenuates drug-primed liver hypertrophy but not Mallory body formation[J]. FEBS letters, 2006, 580(9): 2351-2357.
[8] Beazley K E, Banyard D, Lima F, et al. Transglutaminase inhibitors attenuate vascular calcification in a preclinical model[J]. Arteriosclerosis, thrombosis, and vascular biology, 2013, 33(1): 43-51.
KCC009是一种高特异性、不可逆的transglutaminase 2 (TG2)抑制剂，可诱导不依赖于p53的放射增敏作用[1]。KCC009能够破坏胶质母细胞瘤细胞表面的粘附斑复合物，导致细胞迁移能力下降，使细胞对化疗更敏感，从而引发细胞死亡[2]。KCC009已被广泛用于促进胶质瘤和脑膜瘤细胞凋亡，并增强细胞的化疗敏感性[3]。
在体外，用250μM的KCC009预处理1小时，可抑制紫外线照射的角质形成细胞中细胞因子的产生，并降低NF-κB的转录活性[4]。用3.91μM的KCC009预处理24小时，可增加受照射（6Gy）的H1299/WT-p53细胞中p21、Bax、p-caspase-3的表达，并降低Bcl-2和Cyclin D的表达。用1mM的KCC009处理 U87细胞24小时，可诱导细胞凋亡，伴随细胞从培养板上脱落和细胞膜完整性丧失[6]。
在体内，通过腹腔注射KCC009（20mg/kg；每日三次）连续6天，可减轻3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)诱导的小鼠肝脏肥大[7]。每日腹腔注射50mg/kg剂量的KCC009，连续6周，可阻止warfarin诱导的大鼠主动脉组织中总钙增加[8]。