In vitro efficacy of the anticancer drug imatinib on Echinococcus multilocularis larvae

The metacestode stage of Echinococcus multilocularis is the causative agent of alveolar echinococcosis (AE), a lethal zoonosis with very limited treatment options. Chemotherapy of AE currently employs benzimidazoles (BZs); however, these exert only a parasitostatic action in vivo and have to be given life-long. In the search for novel drug targets, we have concentrated on parasite signalling pathways. Here we report significant antiparasitic effects of imatinib, an ABL kinase inhibitor that is in clinical use to treat certain cancers. At concentrations of 25 mu M, imatinib was highly effective in killing Echinococcus stem cells, metacestode vesicles and protoscoleces in vitro. Moreover, already at concentrations as low as 10 mu M, imatinib significantly inhibited the formation of metacestode vesicles from parasite stem cells, inactivated 50% of vesicles after 7 days, and induced morphological alterations in the metacestode upon short-term treatment. We also demonstrate that E. multilocularis larvae express enzymes with high homology to previously identified ABL-like kinases that act as imatinib targets in Schistosoma mansoni. In particular, amino acids known to mediate the binding of imatinib to target kinases are well conserved between human and Echinococcus ABL kinases. Taken together, these data demonstrate effective inactivation of Echinococcus larvae using imatinib concentrations that do not significantly affect cultivated human cells, indicating that imatinib might be a promising alternative to BZs in anti-AE chemotherapy. Furthermore, imatinib can also act as a lead substance for the identification of related compounds with higher antiparasitic activity, the identification of which will be facilitated by the Echinococcus ABL kinase sequences determined in this study. (C) 2012 Elsevier B. V. and the International Society of Chemotherapy. All rights reserved.