In vitro and in vivo effects of 2-methoxyestradiol, either alone or combined with albendazole, against Echinococcus metacestodes.
The metacestode (larval) stage of the tapeworm Echinococcus multilocularis causes alveolar echinococcosis (AE), a mainly hepatic disease characterized by continuous asexual proliferation of metacestodes by exogenous budding, resulting in the tumor-like, infiltrative growth of the parasite lesion. Current chemotherapeutical treatment of AE relies on the use of benzimidazoles (albendazole, mebendazole), but these drugs act parasitostatic rather than parasitocidal, and in case of side effects such as liver toxicity, patients are left without valuable alternatives. 2-ME2 is a natural metabolite of estradiol, with a documented anti-angiogenic and broad spectrum anti-tumour activity. Treatments of in vitro cultured E. multilocularis metacestodes with 2-ME2 (2-10 microM) showed that the drug has an adverse effect on parasite viability. First, 2-ME in vitro treatment downscaled the transcription of the 14-3-3-pro-tumorogenic zeta-isoform in E. multilocularis metacestodes. Second, scanning and transmission electron microscopy showed that the germinal layer of E. multilocularis metacestodes was dramatically damaged following 2-ME2-treatment, and the effect was dose-dependent. Similar results were obtained with E. granulosus metacestodes. Bioassays were performed in mice injected with 2-ME2-treated and albendazole-treated metacestodes, or parasites-treated with both 2-ME and albendazole in combination. These assays indicated that, despite inducing considerable damage in vitro, neither of the drugs was capable of exerting a true parasiticidal effect, but best results were achieved with a combination of both compounds. In vivo treatment in E. multilocularis-infected mice for a period of 6 weeks showed that a combined 2-ME2/albendazole based treatment lead to a reduction in parasite weight, but the results did not show statistical difference from the application of albendazole alone.
Spicher
Martin
M
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Naguleswaran
Arunasalam
A
Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, MS A-525, Indianapolis, IN 46202, USA.
Ortega-Mora
Luis M
LM
Grupo SALUVET, Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain.
Müller
Joachim
J
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Gottstein
Bruno
B
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Hemphill
Andrew
A
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
D000077584:2-Methoxyestradiol; D015766:Albendazole / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology* / Q000627:therapeutic use; D001681:Biological Assay; D004359:Drug Therapy, Combination; D004444:Echinococcosis, Hepatic / Q000188:drug therapy* / Q000469:parasitology; D048210:Echinococcus multilocularis / Q000187:drug effects* / Q000648:ultrastructure; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007814:Larva / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D012756:Sheep; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000627:therapeutic use
D000871:Anthelmintics; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D015766:Albendazole