Thioguanine is an anti-leukemia and immunosuppressant agent, with IC50 values of 40µM and 25μM for recombinant USP2 and coronaviral PLpro, respectively [1]. Thioguanine can be incorporated into CpG sites, affecting methylation of cytosine residues by methyltransferases and reducing the overall methylation level of cytosine[2]. Thioguanine has been widely used to inhibit a wide variety of cancer cells with a high frequency of homozygous deletion of the gene for methylthioadenosine phosphorylase (MTAP) [3].
In vitro, Thioguanine treatment for 48h inhibited the cell viability of MDA-MB-231, HCC1937, and MCF-10A cells with IC50 values of 2.489, 6.3, and 646.5μM, respectively[4]. Thioguanine treatment for 24 hours inhibited Herpes simplex virus 1 (HSV-1) replication in human corneal epithelial cells (HCECs) with an IC50 value of 0.104μM[5]. Treatment with 1µM Thioguanine for 48 hours significantly inhibited DNA polymerase γ replication in HCT116 cells, damaged mitochondrial DNA, and led to mitochondrial dysfunction[6].
In vivo, Thioguanine treatment via oral administration at a dose of 2.5mg/kg/day for 14 days ameliorated dextran sodium sulfate-induced chronic colitis in C57Bl/6 mice [7]. Thioguanine treatment (0.04mg/day; p.o.) for 5 days significantly extended the survival of the mouse model of leptomeningeal carcinomatosis[8].
References:
[1] Chuang S J, Cheng S C, Tang H C, et al. 6-Thioguanine is a noncompetitive and slow binding inhibitor of human deubiquitinating protease USP2[J]. Scientific reports, 2018, 8(1): 3102.
[2] Wang H, Wang Y. 6-Thioguanine perturbs cytosine methylation at the CpG dinucleotide site by DNA methyltransferases in vitro and acts as a DNA demethylating agent in vivo[J]. Biochemistry, 2009, 48(10): 2290-2299.
[3] Munshi P N, Lubin M, Bertino J R. 6-thioguanine: a drug with unrealized potential for cancer therapy[J]. The oncologist, 2014, 19(7): 760-765.
[4] Zhang D, An X, Li Q, et al. Thioguanine induces apoptosis in triple-negative breast cancer by regulating PI3K–AKT pathway[J]. Frontiers in Oncology, 2020, 10: 524922.
[5] Chen D, Liu Y, Zhang F, et al. 6-Thioguanine inhibits herpes simplex virus 1 infection of eyes[J]. Microbiology Spectrum, 2021, 9(3): e00646-21.
[6] Daehn I, Brem R, Barkauskaite E, et al. 6-Thioguanine damages mitochondrial DNA and causes mitochondrial dysfunction in human cells[J]. FEBS letters, 2011, 585(24): 3941-3946.
[7] Oancea I, Movva R, Das I, et al. Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism[J]. Gut, 2017, 66(1): 59-69.
[8] Nakagawa H, Yui Y, Suzuki T, et al. Investigation of 6-thioguanine as a strategy to overcome methotrexate resistance in a mouse model of leptomeningeal carcinomatosis[J]. Journal of Neuro-Oncology, 2026, 176(1): 64.
Thioguanine是一种抗白血病和免疫抑制剂，对重组USP2和冠状病毒PLpro的IC50值分别为40µM和25µM[1]。Thioguanine可被掺入CpG位点，影响甲基转移酶对胞嘧啶残基的甲基化，并降低胞嘧啶的总体甲基化水平[2]。Thioguanine已被广泛用于抑制多种甲基硫代腺苷磷酸化酶（MTAP）基因纯合缺失高频率的癌细胞[3]。
在体外，Thioguanine处理48小时抑制了MDA-MB-231、HCC1937和MCF-10A细胞的活力，IC50值分别为2.489、6.3和646.5µM[4]。Thioguanine处理24小时抑制了单纯疱疹病毒1型（HSV-1）在人角膜上皮细胞（HCECs）中的复制，IC50值为0.104µM[5]。使用1µM的Thioguanine处理48小时，显著抑制了HCT116细胞中的DNA聚合酶γ复制，损伤了线粒体DNA，并导致线粒体功能障碍[5]。
在体内，以每日2.5mg/kg的剂量口服给予Thioguanine 14天，改善了C57Bl/6小鼠中由葡聚糖硫酸钠诱导的慢性结肠炎[7]。Thioguanine处理（每日0.04mg；p.o.）5天，显著延长了Leptomeningeal carcinomatosis小鼠模型的存活时间[8]。