Efecto del Bortezomib sobre los estadíos larvarios de Echinococcus granulosus y su sinergismo con drogas inhibidoras de peptidil-prolil-isomerasas.

NICOLAO MA. CELESTE; BEAS VIVIANA; CUMINO ANDREA C

Ciudad Autónoma de Bs As

Congreso; XXV Reunión Anual de la Sociedad Argentina de Protozoología y Enfermedades Parasitarias; 2012

Sociedad Argentina de Protozoología

Bortezomib (Bz) is a dipeptyl boronic acid, that inhibits the chymotryptic-like proteolytic activity of the β5 subunit of the 26S proteasome (enzyme complex which plays a cellular key role by regulating protein degradation) and induces cell death in a variety of tumor cells. Bz is a FDA-approved drug, which mechanism of cytotoxicity is not well understood. In this work we tested Bz as a new antiechinoccocal compound against the larval stages of Echinococcus granulosus (Eg), the causative agent of human hydatid disease. Bz inhibited parasite viability in the protoscoleces and cysts, in a dose-dependent manner. After 10 days of incubation with Bz 50µM the viability of treated protoscoleces was reduced to 35 ± 30% whereas after 4 days of treatment against in vitro cultures of cyst resulted in detachment of most germinal layers. Ultrastructural damage, determined by scanning electron microscopy, appeared earlier than the viability inhibition, even with lower drug concentrations. Moreover, a considerable synergistic effect on protoscoleces and cysts viability was found using a combination of Bz plus prolyl isomerase inhibitors such as cyclosporin A (CsA) and rapamycin (Rp). After 10 days of incubation with Bz 25µM plus CsA 25µM or Rp 25µM the viability of treated protoscoleces was reduced to 14 ± 20% and 4.3 ± 6.6 %, respectively. The induction of complete autophagic flux was studied by the accumulation of acidic organelles and the transcriptional and translational expression of the key genes of the pathway (atg6, atg8 and LC3, atg12, atg9 and atg18). These results reflect that, the proteasome blockage and the protein folding inhibition could carry out endoplasmic reticulum stress and unfolded protein responses, promoting the cell death in the larval stage of Eg, contributing to identification of new therapeutic targets for the chemotherapy of cystic echinococcosis.