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Antimicrobial Agents and Chemotherapy, November 2006, p. 3770-3778, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00578-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

In Vitro Metacestodicidal Activities of Genistein and Other Isoflavones against Echinococcus multilocularis and Echinococcus granulosus

Arunasalam Naguleswaran,^1* Martin Spicher,¹ Nathalie Vonlaufen,¹ Luis M. Ortega-Mora,² Paul Torgerson,³ Bruno Gottstein,¹ and Andrew Hemphill^1*

Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland,¹ Grupo SALUVET, Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain,² Institute of Parasitology, Vetsuisse Faculty, University of Zürich, Winterthurstrasse 266a, CH-8057 Zürich, Switzerland³

Received 10 May 2006/ Returned for modification 26 June 2006/ Accepted 23 August 2006

Echinococcus multilocularis and Echinococcus granulosus metacestode infections in humans cause alveolar echinococcosis and cystic echinococcosis, respectively, in which metacestode development in visceral organs often results in particular organ failure. Further, cystic hydatidosis in farm animals causes severe economic losses. Although benzimidazole derivatives such as mebendazole and albendazole are being used as therapeutic agents, there is often no complete recovery after treatment. Hence, in searching for novel treatment options, we examined the in vitro efficacies of a number of isoflavones against Echinococcus metacestodes and protoscoleces. The most prominent isoflavone, genistein, exhibits significant metacestodicidal activity in vitro. However, genistein binds to the estrogen receptor and can thus induce estrogenic effects, which is a major concern during long-term chemotherapy. We have therefore investigated the activities of a number of synthetic genistein derivatives carrying a modified estrogen receptor binding site. One of these, Rm6423, induced dramatic breakdown of the structural integrity of the metacestode germinal layer of both species within 5 to 7 days of in vitro treatment. Further, examination of the culture medium revealed increased leakage of parasite proteins into the medium during treatment, but zymography demonstrated a decrease in the activity of metalloproteases. Moreover, two of the genistein derivatives, Rm6423 and Rm6426, induced considerable damage in E. granulosus protoscoleces, rendering them nonviable. These findings demonstrate that synthetic isoflavones exhibit distinct in vitro effects on Echinococcus metacestodes and protoscoleces, which could potentially be exploited further for the development of novel chemotherapeutical tools against larval-stage Echinococcus infection.

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* Corresponding author. Mailing address: Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland. Phone: 41 31 6312384. Fax: 41 31 6312477. E-mail for Andrew Hemphill: hemphill{at}ipa.unibe.ch. E-mail for Arunasalam Naguleswaran: nagul{at}ipa.unibe.ch.

Published ahead of print on 5 September 2006.

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Antimicrobial Agents and Chemotherapy, November 2006, p. 3770-3778, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00578-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.