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

Abstract

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.Echinococcosis is a cosmopolitan zoonotic disease in ungulates and humans that is acquired by infection with the members of the genus Echinococcus at larval stages. Cystic echinococcosis (CE), the causative agent of which is Echinococcus granulosus, is distributed worldwide. In contrast, alveolar echinococcosis (AE) and Echinococcus multilocularis are generally confined to the Northern hemisphere (8). Dogs and foxes are the major definitive hosts (of E. granulosus and E. multilocularis, respectively). After ingestion of eggs, each containing a single oncosphere, by the host, E. granulosus metacestodes normally develop as single fluid-filled unilocular metacestodes, whereas E. multilocularis metacestodes are characterized by exogenous budding and form multilocular conglomerates that exhibit typical features of tumor-like proliferation. Growth and/or proliferation of metacestodes over a long period of time leads to the development of space-occupying lesions, causes organ malfunction, and eventually leads to death (14,26).The preferred treatment strategy for CE and AE is radical resection of the parasitic mass (26). However, in inoperable cases, chemotherapy is the only option. Benzimidazole carbamate deri...

Innovative chemotherapeutical treatment options for alveolar and cystic echinococcosis

“…Besides other targets, genistein acts on a number of signalling pathways by functioning as a kinase inhibitor (tyrosine kinase, MAP kinase, ribosomal S6 kinase). Recent studies have shown that genistein is highly effective against E. multilocularis metacestodes in vitro (Naguleswaran et al 2006). However, genistein has a disadvantage, in that it also exerts oestrogenic effects by binding to oestrogen receptor-b, which renders genistein unfavourable for long-term treatment.…”

“…Therefore, a number of isoflavonoids that do not carry this hydroxylgroup have been tested in vitro and do not meet the steric requirements to bind to the oestrogen receptor-beta. One of these compounds, Rm6423, exhibits a pronounced anti-parasitic activity against E. multilocularis metacestodes as well as against E. granulosus metacestodes and protoscoleces (Naguleswaran et al 2006). Moreover, an examination of culture medium revealed increased leakage of parasite proteins into the medium during treatment, and zymography demonstrated a loss of the activity of metalloproteases.…”

Alveolar and cystic echinococcosis: towards novel chemotherapeutical treatment options

“…We have therefore tested a number of isoflavonoids in vitro, which do not carry this hydroxylgroup and therefore do not meet the steric requirements to bind to the oestrogen receptor-b. One of these compounds, Rm6423, exhibits pronounced antiparasitic activity against E. multilocularis metacestodes, as well as against E. granulosus metacestodes and protoscoleces (Naguleswaran et al, 2006). Further, examination of culture medium revealed increased leakage of parasite proteins into the medium during treatment, and zymography demonstrated a loss in the activity of metalloproteases.…”

Viability loss and ultrastructural changes on protoscolices of human hydatid cysts induced by retinoic acid

“…However, no ideal (both effective and safe) scolicidal agent has been deviced yet. The unacceptable sideeffects of the scolicidal agents cause limitation to their use (Naguleswaran et al, 2006). Surgery (radical or conservative) is usually complemented by pre and/or post-surgical chemotherapy.…”