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.