NSC 74859 is a selective STAT3 inhibitor with an IC50 of 86μM[1]. STAT3(Signal Transducer and activator of Transcription 3), a pivotal transcription factor governing cell proliferation, survival and immune responses, is aberrantly activated in numerous cancers and inflammatory diseases[2]. NSC 74859 is mainly applied in tumor-targeted therapy, tumor immunology research[3][4].
In vitro, NSC 74859 (100μM; 48h) significantly inhibited STAT3 Tyr705 phosphorylation in HepG2, SK-HEP1 and Huh-7 human hepatoma cells, and synergically enhanced the antiproliferative activity of cetuximab[5].
In vivo, NSC 74859 (10mg/kg; p.o.; every other day for 14 days) attenuated cardiac allograft rejection and prolonged survival in mice by reducing infiltration of CD4⁺, CD8⁺ T cells and CD14⁺ monocytes/macrophages and by down-regulating IL-2, IL-15 and IL-6 expression within the graft[6]. NSC 74859(2.5mg/kg; i.p.; 16 weeks) significantly reduced renal collagen deposition, down-regulated fibrotic molecules (TGF-β1, ACE, AT1, VEGF), attenuated albuminuria, and reversed tubulointerstitial fibrosis and functional impairment in streptozocin-induced diabetic mice[7].
References:
[1] Siddiquee K, Zhang S, Guida WC, et al. Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activity. Proc Natl Acad Sci U S A. 2007;104(18):7391-7396.
[2] Zou S, Tong Q, Liu B, Huang W, Tian Y, Fu X. Targeting STAT3 in Cancer Immunotherapy. Mol Cancer. 2020;19(1):145.
[3] Lin L, Amin R, Gallicano GI, et al. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling. Oncogene. 2009;28(7):961-972.
[4] Brady MT, Miller A, Sait SN, et al. Down-regulation of signal transducer and activator of transcription 3 improves human acute myeloid leukemia-derived dendritic cell function. Leuk Res. 2013;37(7):822-828.
[5] Chen W, Shen X, Xia X, et al. NSC 74859-mediated inhibition of STAT3 enhances the anti-proliferative activity of cetuximab in hepatocellular carcinoma. Liver Int. 2012;32(1):70-77.
[6] Lai Y, Kuang F, Shan Z, Liu H. A New Concept of the Old Inhibitor NSC 74859 in Alleviating Cardiac Allograft Rejection and Extending Allograft Survival in Mice. Ann Transplant. 2017;22:656-662.
[7] Zheng C, Huang L, Luo W, et al. Inhibition of STAT3 in tubular epithelial cells prevents kidney fibrosis and nephropathy in STZ-induced diabetic mice. Cell Death Dis. 2019;10(11):848.
NSC 74859是一种选择性STAT3抑制剂，IC50为86μM[1]。STAT3（信号转导与转录激活因子 3）是调控细胞增殖、存活及免疫反应的关键转录因子，其异常激活与多种癌症和炎症性疾病密切相关[2]。NSC 74859主要应用于肿瘤靶向治疗及肿瘤免疫学研究[3][4]。
体外实验中，NSC 74859（100μM；48h）显著抑制HepG2、SK-HEP1和Huh-7 三种人肝癌细胞的STAT3 Tyr705磷酸化，并与西妥昔单抗协同增强抗增殖活性[5]。
体内实验中，NSC 74859（10mg/kg；口服；隔日一次，共14天）通过减少心脏同种异体移植物内CD4⁺、CD8⁺ T细胞及CD14⁺单核/巨噬细胞的浸润，并下调IL-2、IL-15和IL-6的表达，显著减轻小鼠心脏排斥反应并延长移植物存活时间[6]。NSC 74859（2.5mg/kg；腹腔注射；16周）显著降低链脲佐菌素诱导的糖尿病小鼠肾脏胶原沉积，下调纤维化分子（TGF-β1、ACE、AT1、VEGF）表达，减轻蛋白尿，并逆转糖尿病引起的肾小管间质纤维化及功能损伤[7]。