Laboratorio de Zoonosis Parasitarias, Departamento de Biología, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Funes 3350, Nivel Cero, Mar del Plata 7600, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
Parasitología y Enfermedades Parasitarias, Facultad de Ciencias Veterinarias, Universidad Nacional de Rosario, Santa Fe, Argentina, Boulevard Ovidio Lagos 1000, 2170Casilda, Santa Fe, Argentina.
Acta Trop. 2020 Mar;203:105312. doi: 10.1016/j.actatropica.2019.105312. Epub 2019 Dec 20.
Cystic echinococcosis (CE) is a worldwide zoonosis caused by the Echinococcus granulosus larval stage. The currently available therapy for this disease is based on benzimidazoles, which are rarely curative and cause several adverse effects. Therefore, new treatment options are needed. Octreotide (Oct) is a somatostatin analogue which exhibits anti-proliferative and anti-secretory effects over several cancer cell lines expressing somatostatin receptors. Here, we assessed the in vitro pharmacological effect of Oct against the E. granulosus larval stage. The drug caused a significant dose-dependent decrease in the viability of both protoscoleces and metacestodes. SEM and TEM analysis showed ultrastructural damage in both larval forms under drug treatment. Based on this, we investigated the possible presence of an Oct binding receptor in the parasite. The putative somatostatin/allatostatin-like receptor (Eg-s/ast) conserves the characteristic topology and signature sequences of the prototype somatostatin receptor common to vertebrates and is expressed in both metacestodes and protoscoleces. Moreover, Oct treated-parasites showed the presence of autophagic structures and a significant increase in transcriptional expression of autophagy key genes such as Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16. In addition, by in toto immunolocalization assays, an increase in the punctate pattern and Eg-Atg8 protein expression was detected in Oct-treated metacestodes. Subsequently, the combination of Oct and Met had an additive effect on the viability of both larval forms. Our results provide additional evidence for the participation of PI3K/AKT/TOR/autophagy pathway in the Echinococcus survival and suggest the concomitant use of these drugs as potential therapeutic agents in treating of CE.
棘球蚴病（CE）是一种全球性的人畜共患病，由细粒棘球蚴幼虫阶段引起。目前这种疾病的治疗方法基于苯并咪唑类药物，但这些药物很少能治愈疾病，而且会引起多种不良反应。因此，需要新的治疗选择。奥曲肽（Oct）是一种生长抑素类似物，对表达生长抑素受体的多种癌细胞系具有抗增殖和抗分泌作用。在这里，我们评估了 Oct 对细粒棘球蚴幼虫阶段的体外药理作用。该药物导致原头蚴和囊尾蚴的活力明显呈剂量依赖性下降。扫描电镜和透射电镜分析显示，在药物处理下，两种幼虫形式均出现超微结构损伤。基于此，我们研究了寄生虫中是否存在 Oct 结合受体。假定的生长抑素/阿拉托素样受体（Eg-s/ast）保留了特征拓扑结构和特征序列，与脊椎动物的原型生长抑素受体相同，并在囊尾蚴和原头蚴中均有表达。此外，用 Oct 处理的寄生虫表现出自噬结构的存在，以及自噬关键基因如 Eg-atg6、Eg-atg8、Eg-atg12 和 Eg-atg16 的转录表达显著增加。此外，通过整体免疫定位检测，在 Oct 处理的囊尾蚴中检测到点状模式和 Eg-Atg8 蛋白表达增加。随后，Oct 和 Met 的联合使用对两种幼虫形式的活力都有相加作用。我们的结果为 PI3K/AKT/TOR/自噬途径参与棘球蚴的生存提供了额外的证据，并表明同时使用这些药物作为治疗 CE 的潜在治疗药物。
