Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models

Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch-wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC.间变性甲状腺癌（Anaplastic Thyroid Cancer, ATC）是一类罕见且致死性极强的人类恶性肿瘤，多数患者尚无有效治疗方案。尽管可采用化疗、放疗及手术切除等常规治疗手段，该疾病仍几乎呈100%致死性。本研究针对13株ATC细胞系开展体外测试，鉴定出JAK2抑制剂来他替尼（Lestaurtinib）为强效活性化合物。来他替尼在纳摩尔浓度下即可在体外展现出显著的抗增殖活性。此外，通过划痕实验（scratch-wound assay）与集落形成实验（colony formation assay）分别检测，来他替尼可抑制细胞迁移及单细胞克隆形成能力。采用流式细胞术开展药物处理后的细胞周期分析，结果显示来他替尼可使细胞周期阻滞于G2/M期，提示其具备细胞生长抑制活性。采用鸡胚绒毛尿囊膜（chick chorioallantoic membrane, CAM）异种移植模型开展的体内研究显示，通过能量多普勒超声成像（power Doppler ultrasound imaging）检测，来他替尼治疗可显著降低终末肿瘤体积与血管生成水平。综上，本研究证实来他替尼是一种强效抗增殖剂，具有潜在抗血管生成活性，有望作为ATC的靶向治疗手段开展进一步研究。