In vitro metacestodicidal activities of genistein and other isoflavones against Echinococcus multilocularis and Echinococcus granulosus.
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.
Naguleswaran
Arunasalam
A
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Spicher
Martin
M
Vonlaufen
Nathalie
N
Ortega-Mora
Luis M
LM
Torgerson
Paul
P
Gottstein
Bruno
B
Hemphill
Andrew
A
D000818:Animals; D000923:Anticestodal Agents; D015153:Blotting, Western; D004443:Echinococcosis / Q000188:drug therapy / Q000469:parasitology; D048209:Echinococcus granulosus / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D048210:Echinococcus multilocularis / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D004591:Electrophoresis, Polyacrylamide Gel; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D007529:Isoflavones / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects; D045726:Metalloproteases / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects
D000923:Anticestodal Agents; D007529:Isoflavones; D004815:Epidermal Growth Factor; D019833:Genistein; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D045726:Metalloproteases