Preliminary investigation of the relationship between angiogenesis and growth of E. multilocularis metacestodes and anti-hydatid effect of antiangiogenic agent

Alveolar echinococcosis (AE), caused by Echinococcus multilocularis (E. multilocularis, E.m), is a lethal human parasitosis and always referred to as a tumor-like hydatid disease because of its kind of similarity with tumors in biological features and pathological manifestations. Current primary treatment options for human AE include radical surgery and chemotherapy. For chemotherapy, present licensed anti-human AE chemotherapeutics primarily involve albendazole (ABZ) and mebendazole (MBZ). However, the parasitostatic rather than parasitocidal actions of the agents always lead to a low cure rate and an unavoidable long-term application for AE patients. Thus, new chemotherapeutic agents with high efficacy and low toxicity are urgently needed for the control of echinococcosis. Apatinib, as a novel vascular endothelial growth factor receptor (VEGFR)-targeted therapeutic agent, has been legitimately applied to patients’ terminal cancers and shows encouraging effects. The experiment found that E.m metacestodes appeared active angiogenesis with their growth, indicating a close link between the development and the angiogenesis in AE. As such, in this study we investigated the potential of apatinib as a VEGFR-2 inhibitor against E. m. In addition, the secondary infectious pathway of AE in intermediate hosts remains a controversial issue. The close link between the angiogenesis and the growth and metastasis of E.m metacestodes was demonstrated and the possibility of AE metastasis via lymphohaematogenous pathway was verified. The preliminary in vitro experiment also showed that apatinib could dose-dependently eradicate E.m- PSCx. No significant cytotoxicity at an effective anti-E.m-PSCx concentration of the drug was exhibited.泡型棘球蚴病（Alveolar echinococcosis, AE）是由多房棘球绦虫（Echinococcus multilocularis, 简称E. multilocularis、E.m）引发的致死性人体寄生虫病，因其生物学特征与病理表现与肿瘤具有相似性，常被称为肿瘤样棘球蚴病。当前人体AE的主要治疗手段包括根治性手术与化学治疗（化疗）。在化疗领域，目前获批用于抗人体AE的化疗药物主要为阿苯达唑（albendazole, ABZ）与甲苯达唑（mebendazole, MBZ）。然而，此类药物仅能发挥抑虫作用而非杀虫作用，常导致患者治愈率偏低，且需长期持续用药。因此，亟需开发高效低毒的新型化疗药物以防控棘球蚴病。阿帕替尼（Apatinib）是一种新型血管内皮生长因子受体（vascular endothelial growth factor receptor, VEGFR）靶向治疗药物，已获批用于晚期癌症患者的治疗，且疗效喜人。研究发现，多房棘球绦虫的中绦期幼虫在生长过程中会出现活跃的血管生成现象，提示AE的发生发展与血管生成密切相关。基于此，本研究探讨了作为VEGFR-2抑制剂的阿帕替尼抗E.m的潜力。此外，AE在中间宿主中的继发感染途径仍存在学术争议。本研究证实了多房棘球绦虫中绦期幼虫的血管生成与其生长及转移之间的紧密关联，并验证了AE可通过淋巴血行途径发生转移的可能性。体外预实验结果显示，阿帕替尼可剂量依赖性地杀灭E.m-PSCx，且在达到有效抗E.m-PSCx的药物浓度时，未表现出明显的细胞毒性。