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Evaluation of kinase-inhibitors nilotinib and everolimus against alveolar echinococcosis in vitro and in a mouse model.
Exp Parasitol. 2018 May; 188:65-72.EP

Abstract

Infection with the larval stage (metacestode) of the fox tapeworm Echinococcus multilocularis leads to a primary hepatic disease referred to as alveolar echinococcosis (AE). The progressive disease can be lethal if untreated. In cases where complete parasite resection by surgery is not feasible, the current treatment regimens of AE consist of chemotherapy with the parasitostatic benzimidazoles albendazole or mebendazole over decades. Kinase-inhibitors currently administered in various cancer treatments are of increasing interest also as anti-parasitic drugs due to previous promising in vitro results. In order to search for novel drug targets and treatment regimens, nilotinib (AMN107; Tasigna®), an Abl-tyrosine kinase inhibitor and everolimus (RAD001; Afinitor®), a serine/threonine-kinase inhibitor, were tested for their treatment efficacy against metacestode vesicles of E. multilocularis in vitro and in BALB/c mice. In vitro treatment with 200 μM nilotinib caused drug-induced alterations after 12 days, and everolimus exerted parasite damage at concentrations dosing from 40 to 100 μM after 5 and 12 days of in vitro exposure. Nilotinib (100 mg/kg) + erythromycin (to increase nilotinib plasma levels: 10 mg/kg intraperitoneal) or everolimus (5 mg/kg) were formulated in honey and administered daily for three weeks and subsequently twice a week for an additional three weeks in experimentally infected mice. Treatments did not result in any reduction of parasite growth compared to untreated control groups, whereas oral treatment with albendazole (200 mg/kg) was highly effective. Combined application of the kinase-inhibitors with albendazole did not lead to a synergistic or additive treatment efficacy compared to albendazole treatment alone. These results show that neither nilotinib nor everolimus represent valuable alternatives to the current treatment regimens against AE.

Authors+Show Affiliations

Institute of Parasitology, Vetsuisse Faculty, University of Zurich, Switzerland.Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland.Division of Gastroenterology and Hepatology, University Hospital of Zurich, Switzerland.Institute of Parasitology, Vetsuisse Faculty, University of Berne, Switzerland.Institute of Parasitology, Vetsuisse Faculty, University of Zurich, Switzerland. Electronic address: deplazesp@access.uzh.ch.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29625098

Citation

Joekel, Deborah E., et al. "Evaluation of Kinase-inhibitors Nilotinib and Everolimus Against Alveolar Echinococcosis in Vitro and in a Mouse Model." Experimental Parasitology, vol. 188, 2018, pp. 65-72.
Joekel DE, Lundström-Stadelmann B, Müllhaupt B, et al. Evaluation of kinase-inhibitors nilotinib and everolimus against alveolar echinococcosis in vitro and in a mouse model. Exp Parasitol. 2018;188:65-72.
Joekel, D. E., Lundström-Stadelmann, B., Müllhaupt, B., Hemphill, A., & Deplazes, P. (2018). Evaluation of kinase-inhibitors nilotinib and everolimus against alveolar echinococcosis in vitro and in a mouse model. Experimental Parasitology, 188, 65-72. https://doi.org/10.1016/j.exppara.2018.04.002
Joekel DE, et al. Evaluation of Kinase-inhibitors Nilotinib and Everolimus Against Alveolar Echinococcosis in Vitro and in a Mouse Model. Exp Parasitol. 2018;188:65-72. PubMed PMID: 29625098.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of kinase-inhibitors nilotinib and everolimus against alveolar echinococcosis in vitro and in a mouse model. AU - Joekel,Deborah E, AU - Lundström-Stadelmann,Britta, AU - Müllhaupt,Beat, AU - Hemphill,Andrew, AU - Deplazes,Peter, Y1 - 2018/04/03/ PY - 2017/10/31/received PY - 2018/03/07/revised PY - 2018/04/02/accepted PY - 2018/4/7/pubmed PY - 2018/5/5/medline PY - 2018/4/7/entrez KW - Echinococcosis KW - Echinococcus multilocularis KW - Oncology drugs KW - Protein kinases SP - 65 EP - 72 JF - Experimental parasitology JO - Exp. Parasitol. VL - 188 N2 - Infection with the larval stage (metacestode) of the fox tapeworm Echinococcus multilocularis leads to a primary hepatic disease referred to as alveolar echinococcosis (AE). The progressive disease can be lethal if untreated. In cases where complete parasite resection by surgery is not feasible, the current treatment regimens of AE consist of chemotherapy with the parasitostatic benzimidazoles albendazole or mebendazole over decades. Kinase-inhibitors currently administered in various cancer treatments are of increasing interest also as anti-parasitic drugs due to previous promising in vitro results. In order to search for novel drug targets and treatment regimens, nilotinib (AMN107; Tasigna®), an Abl-tyrosine kinase inhibitor and everolimus (RAD001; Afinitor®), a serine/threonine-kinase inhibitor, were tested for their treatment efficacy against metacestode vesicles of E. multilocularis in vitro and in BALB/c mice. In vitro treatment with 200 μM nilotinib caused drug-induced alterations after 12 days, and everolimus exerted parasite damage at concentrations dosing from 40 to 100 μM after 5 and 12 days of in vitro exposure. Nilotinib (100 mg/kg) + erythromycin (to increase nilotinib plasma levels: 10 mg/kg intraperitoneal) or everolimus (5 mg/kg) were formulated in honey and administered daily for three weeks and subsequently twice a week for an additional three weeks in experimentally infected mice. Treatments did not result in any reduction of parasite growth compared to untreated control groups, whereas oral treatment with albendazole (200 mg/kg) was highly effective. Combined application of the kinase-inhibitors with albendazole did not lead to a synergistic or additive treatment efficacy compared to albendazole treatment alone. These results show that neither nilotinib nor everolimus represent valuable alternatives to the current treatment regimens against AE. SN - 1090-2449 UR - https://www.unboundmedicine.com/medline/citation/29625098/Evaluation_of_kinase_inhibitors_nilotinib_and_everolimus_against_alveolar_echinococcosis_in_vitro_and_in_a_mouse_model_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4894(17)30572-6 DB - PRIME DP - Unbound Medicine ER -