In Vitro and In Vivo Effects of Tamoxifen against Larval Stage Echinococcus granulosus

Abstract

Cystic echinococcosis is a zoonotic infection caused by the larval stage of the cestodeEchinococcus granulosus. Chemotherapy currently employs benzimidazoles; however, 40% of cases do not respond favorably. With regard to these difficulties, novel therapeutic tools are needed to optimize treatment in humans. The aim of this work was to explore thein vitroandin vivoeffects of tamoxifen (TAM) againstE. granulosus. In addition, possible mechanisms for the susceptibility of TAM are discussed in relation to calcium homeostasis, P-glycoprotein inhibition, and antagonist effects on a putative steroid receptor. After 24 h of treatment, TAM, at a low micromolar concentration range (10 to 50 μM), inhibited the survival ofE. granulosusprotoscoleces and metacestodes. Moreover, we demonstrated the chemotherapeutic and chemopreventive pharmacological effects of the drug. At a dose rate of 20 mg/kg of body weight, TAM induced protection against the infection in mice. In the clinical efficacy studies, a reduction in cyst weight was observed after the administration of 20 mg/kg in mice with cysts developed during 3 or 6 months, compared to that of those collected from control mice. Since the collateral effects of high TAM doses have been largely documented in clinical trials, the use of low doses of this drug as a short-term therapy may be a novel alternative approach for human cystic echinococcosis treatment.

Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in Echinococcus granulosus larval stage

“…For this reason, a low expression of Eg- ire and a high Eg- grp 78 expression could account for a reduced capacity to elicit apoptosis in the germinal cells of the cestode. On the other hand, high basal expression of chaperones in protoscoleces could be related to the regulation of Ca 2+ homeostasis, an important process in this parasite [ 27 , 30 ]. Also, calnexin (shown in Fig 2 ) and calreticulin can regulate the quality control of glycoproteins in the ER, which are crucial to generate the laminar layer in E .…”

“…Otherwise, E . granulosus metacestodes (10–20 cysts for each drug treatment) were obtained from the peritoneal cavities of CF-1 mice after intraperitoneal infection with protoscoleces [ 30 ]. In vitro protoscolex and metacestode treatments were assayed with rapamycin (Rm, Calbiochem, USA) and Bortezomib (Bz, Janssen-Cilag, Germany) dissolved in dimethyl sulfoxide (DMSO).…”

Selenophene and thiophene-core estrogen receptor ligands that inhibit motility and development of parasitic stages of Haemonchus contortus

“…Previously, SERMs, such as tamoxifen and raloxifene, have been shown to reduce the burden of parasitic cestodes in experimental infections in hamsters or mice [ 18 , 20 , 21 , 23 ]. In particular, tamoxifen is believed to interfere with the ER pathway in the parasite, as high levels of estrogen have been shown to increase the viability and reproductive rate of the asexual (cysticercus) stage of T. crassiceps , and treatment with this drug was shown to reduce the production of ER-like proteins [ 22 , 23 ].…”

“…In public-private and cross-disciplinary partnerships, we have developed an efficient whole-organism drug-screening assay for H. contortus for the discovery and subsequent repurposing of compounds to parasitic nematodes [ 14 – 16 ]. Interestingly, recent reports have shown that some selective estrogen receptor modulators (SERMs) have considerable activity against protistan parasites, such as Leishmania [ 17 – 19 ] and cestodes, including Echinococcus granulosus, Taenia crassiceps and T. solium [ 20 , 21 ]. In these cestodes, estrogen receptor-like proteins have been identified, and the mammalian ligand (17-β-estradiol) has been shown to enhance the (asexual) reproductive rate of T. crassiceps [ 22 , 23 ].…”

Construction of In Vivo Fluorescent Imaging of <i>Echinococcus granulosus</i> in a Mouse Model

“…Previous research adopted mouse models, especially peritoneal implantation, in studies on E. granulosus describing immunology and susceptibility testing assays [ 25 , 26 ]. None of these studies discussed the use of optical molecular imaging, which yields images reflecting the growth, metastasis, and in vivo mechanisms of diseases present within the context of physiologically authentic environments in a noninvasive manner [ 14 ].…”