Toyocamycin

Toyocamycin is an adenosine analog and an inhibitor of XBP1. Toyocamycin is also a specific inhibitor of Cyclin-dependent kinase 9 (CDK9), with an IC50 value of 79nM[1]. Toyocamycin is a potent inhibitor of RNA autocleavage and phosphatidylinositol kinase in mammalian cells[2]. Toyocamycin is a nucleoside antibiotic that can selectively inhibit CDC2 kinase with an IC50 value of 0.88µM and does not affect other protein kinases [3].

In vitro, Toyocamycin (250nM) treated YB5 cells for 2-96 hours, significantly inducing time-dependent gene expression changes, increasing the levels of differentially expressed genes, and also inducing cells to express GFP[1]. Toyocamycin (250nM) treated colon cancer cell lines for 48 hours and significantly inhibited CDK9 enzyme activity[1]. Toyocamycin (0-100nM) treated human prostate cancer PC-3 cells, significantly reducing cell viability in a dose- and time-dependent manner and inducing apoptosis through the mitochondrial pathway [4].

In vivo, Toyocamycin significantly reduced tumor volume after intraperitoneal injection twice a week (0.5mg/kg) or once a week (1.0 mg/kg) in multiple myeloma transplanted mice, and the two injection methods had anti-tumor effects. There is no significant difference[5]. Toyocamycin (0.25 mg/kg) treated by intraperitoneal injection in mice with non-alcoholic fatty liver disease reduced serum liver dysfunction indicators as well as serum total cholesterol and triglyceride levels, and reduced the expression of steatosis and lipogenesis genes[6].

References:
[1]Pandey S, Djibo R, Darracq A, et al. Selective CDK9 inhibition by natural compound toyocamycin in cancer cells[J]. Cancers, 2022, 14(14): 3340.
[2] Nishioka H, Sawa T, Hamada M, et al. Inhibition of phosphatidylinositol kinase by toyocamycin[J]. The Journal of antibiotics, 1990, 43(12): 1586-1589.
[3] Park S G, Cheon J Y, Lee Y H, et al. A specific inhibitor of cyclin-dependent protein kinases, CDC2 and CDK2[J]. Molecules and cells, 1996, 6(6): 679-683.
[4] Park S G, Kim S H, Kim K Y, et al. Toyocamycin induces apoptosis via the crosstalk between reactive oxygen species and p38/ERK MAPKs signaling pathway in human prostate cancer PC-3 cells[J]. Pharmacological Reports, 2017, 69(1): 90-96.
[5]Ri M, Tashiro E, Oikawa D, et al. Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing[J]. Blood cancer journal, 2012, 2(7): e79-e79.
[6]Takahara I, Akazawa Y, Tabuchi M, et al. Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice[J]. PloS one, 2017, 12(3): e0170591.

Toyocamycin是一种腺苷类似物,是XBP1的抑制剂。Toyocamycin也是细胞周期蛋白依赖性激酶 9(CDK9)的特异性抑制剂,IC50值为79 nM[1]。Toyocamycin是哺乳动物细胞中 RNA自裂解和磷脂酰肌醇激酶的有效抑制剂[2]。Toyocamycin是一种核苷类抗生素,可以选择性抑制CDC2激酶,IC50值为0.88µM,不影响其他蛋白激酶[3]。

在体外,Toyocamycin(250nM)处理YB5细胞2-96h,显著诱导了时间依赖性的基因表达变化,提高了差异表达基因的水平,还可以诱导细胞表达GFP[1]。Toyocamycin(250nM)处理结肠癌细胞系48h,显著抑制了 CDK9 酶活性[1]。Toyocamycin(0-100nM)处理人前列腺癌PC-3细胞,以剂量和时间依赖性方式显著降低了细胞活力,并通过线粒体途径诱导了细胞凋亡[4]。

在体内,Toyocamycin每周腹腔注射两次(0.5 mg/kg)或每周一次(1.0 mg/kg)治疗多发性骨髓瘤移植小鼠后,显著减小了肿瘤体积,两种注射方式抑瘤效果无明显差异[5]。Toyocamycin(0.25 mg/kg)通过腹腔注射治疗非酒精性脂肪肝病小鼠,降低了血清肝功能障碍指标以及血清总胆固醇和甘油三酯水平,减少了脂肪变性和脂肪生成基因的表达[6]。