In vitro anti-echinococcal activity of octreotide: additive effect of metformin linked to autophagy

LOOS, JULIA A.; NEGRO, PERLA S.; CUMINO, ANDREA C.

ACTA TROPICA

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2020

0001-706X

Cystic echinococcosis (CE) is a worldwide zoonosis caused by the larval stage of the cestode Echinococcus granulosus. 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, both endocrine and non-endocrine, expressing somatostatin receptors. In this study, we assessed the in vitro pharmacological effect of Oct against the larval stage of E. granulosus. The drug caused a significant dose-dependent decrease in the viability of both protoscoleces and metacestodes. In parallel, SEM and TEM analysis showed ultrastructural damage in both larval forms under drug treatment. Based on this, we proceeded to investigate 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 in metacestodes and protoscoleces. Moreover, Oct significantly increased the transcriptional expression of autophagy key genes such as Eg-atg6, Eg-atg8, Eg-atg12 and Eg-atg16 in both larval forms. In accordance with these findings, ultrastructural studies also showed the presence of autophagic structures in drug treated-protoscoleces. 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, based on the fact that Oct inhibits the PI3K-AKT pathway and metformin (Met) activates AMPK and on the hypothesis that an additional inhibition of TORC1 would increase death of the parasite, the combination of Oct together with Met was evaluated. The combination had an additive effect on the viability of both larval forms. Our results provides 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.