Thiostrepton

Thiostrepton, an antibiotic derived from Streptomyces azureus, is a specific inhibitor of FoxM1^[1]. Thiostrepton exhibits anticancer efficacy and pronounced anti-inflammatory effects^[2][3][4][7].

In vitro, Thiostrepton (0-5μM) incubation on non–small‐cell lung cancer cells (NSCLCs) for 14 days suppressed cellular viability and colony‐forming ability in a dose‐dependent manner with an IC₅₀ value of 0.05μM and significantly reduced the migration capability^[3]. Thiostrepton (1µM) treatment on Ewing's sarcoma for 48h altered cell cycle with a decrease in the percentage of the cell populations traversing through S-phase and the accumulation of cells in either the G1 or the G2-M phase. Thiostrepton also inhibited the mRNA and protein expression of both FoxM1 and EWS/FLI1^[4].

In vivo, Thiostrepton (17mg/kg) were intraperitoneally injected into pancreatic cancer MIAPaCa-2 cells xenograft BALB/c nude mice with or without Fer-1 (5mg/kg) three times a week for 3 weeks. Thiostrepton treatment lowered FOXM1, STAT3, p-STAT3, GPX4 and Ki67 staining. Thiostrepton inhibited tumour growth, and Fer-1, a ferroptosis inhibitor, reversed this effect^[5]. Thiostrepton (30mg/kg) was administered daily into an human endometrial adenocarcinoma HEC-1A cells xenograft mice model with or without weekly carboplatin (80mg/kg, reduced to 20mg/kg from day 22) for 5 weeks. Thiostrepton alone showed no significant antitumor activity but enhances sensitivity to carboplatin in vivo^[6]. Thiostrepton (20mg/kg) was administered into cecal ligation and puncture-induced sepsis model mice intraperitoneally and monitored for survival up to 7 days. Thiostrepton improved survival in the murine model by reducing pro-inflammatory markers, reducing plasma creatinine and reducing intravascular and peritoneal bacterial burden^[7].

References:
[1] Korkmaz F D, Turacli I D, Esendagli G, Ekmekci A. Effects of thiostrepton alone or in combination with selumetinib on triple-negative breast cancer metastasis. Mol Biol Rep. 2022 Nov;49(11):10387-10397.
[2] Asikaer A, Sun C, Shen Y. Thiostrepton: multifaceted biological activities and its applications in treatment of inflammatory diseases. Inflammopharmacology. 2025 Jan;33(1):183-194.
[3] Huang T H, Wu A T H, Cheng T S, et al. In silico identification of thiostrepton as an inhibitor of cancer stem cell growth and an enhancer for chemotherapy in non-small-cell lung cancer.J Cell Mol Med. 2019 Dec;23(12):8184-8195.
[4] Sengupta A, Rahman M, Lozano S M, Tirado O M, Notario V. The dual inhibitory effect of thiostrepton on FoxM1 and EWS/FLI1 provides a novel therapeutic option for Ewing's sarcoma. Int J Oncol. 2013 Sep;43(3):803-12.
[5] Zhang W F, Gong M Y, Zhang W N, et al. Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling. Cell Death Dis. 2022 Jul 20;13(7):630.
[6] Zhang X, Cheng L H, Minn K, et al. Targeting of mutant p53-induced FoxM1 with thiostrepton induces cytotoxicity and enhances carboplatin sensitivity in cancer cells. Oncotarget. 2014 Nov 30;5(22):11365-80.
[7] Esparza K, Oliveira S D, Castellon M, Minshall R D, Onyuksel H. Thiostrepton-Nanomedicine, a TLR9 Inhibitor, Attenuates Sepsis-Induced Inflammation in Mice. Mediators Inflamm. 2023 Aug 24:2023:4035516.

Thiostrepton，一种源自Streptomyces azureus的抗生素，是FoxM1的特异性抑制剂^[1]。Thiostrepton表现出抗癌功效和显著的抗炎作用^[2][3][4][7]。

体外实验中，Thiostrepton（0–5μM）作用于非小细胞肺癌细胞（NSCLCs）14天，呈剂量依赖性抑制细胞活力和集落形成能力，IC₅₀值为0.05μM，并显著降低细胞迁移能力^[3]。Thiostrepton（1μM）处理尤因肉瘤48小时，改变细胞周期，减少S期细胞比例，并使细胞阻滞于G1或G2-M期，同时抑制FoxM1和EWS/FLI1的mRNA及蛋白表达^[4]。

体内实验中，将Thiostrepton（17mg/kg）单独或与Fer-1（5mg/kg）联合，每周3次腹腔注射于MIAPaCa-2异种移植BALB/c裸鼠，持续3周。Thiostrepton降低FOXM1、STAT3、p-STAT3、GPX4和Ki67染色，抑制肿瘤生长，而铁死亡抑制剂Fer-1可逆转该效应^[5]。将Thiostrepton（30mg/kg）单独或联合卡铂（80mg/kg，第22天起减至20mg/kg）治疗人子宫内膜腺癌细胞HEC-1A腹腔异种移植小鼠模型，每日给予，持续5周；单用Thiostrepton未显显著抗肿瘤活性，但可增强卡铂在小鼠模型中的敏感性^[6]。腹腔注射Thiostrepton（20mg/kg）于盲肠结扎穿孔诱导的脓毒症小鼠模型中，并监测生存至7天。Thiostrepton通过降低促炎标志物、血浆肌酐及血管内和腹腔细菌负荷，提高小鼠生存率^[7]。