Journal
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
Volume 4, Issue 3, Pages 287-295Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ijpddr.2014.07.005
Keywords
Schistosoma mansoni; Protein tyrosine kinase (PTK); Abl tyrosine kinase (Abl); Imatinib (Gleevec, Glivec, STI-571); In vitro culture; Serum albumin (SA); alpha-1 acidic glycoprotein (AGP); Erythromycin
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Funding
- Deutsche Forschungsgemeinschaft [GR 1549/5-1]
- Bill and Melinda Gates Foundation Grant through the Grand Challenges Exploration Initiative [OPP1024324]
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R21AI107390]
- Bill and Melinda Gates Foundation [OPP1024324] Funding Source: Bill and Melinda Gates Foundation
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In the search for new drugs and drug targets to treat the flatworm disease schistosomiasis, protein kinases (PKs) have come under particular scrutiny because of their essential roles in developmental and physiological processes in schistosome parasites. In this context the application of the anti-cancer Abl tyrosine kinase (TK) inhibitor Imatinib (Gleevec/Glivec; STI-571) to adult Schistosoma mansoni in vitro has indicated negative effects on diverse physiological processes including survival. Motivated by these in vitro findings, we performed in vivo experiments in rodent models of S. mansoni infection. Unexpectedly, Imatinib had no effect on worm burden or egg-production. We found that the blood components serum albumin (SA) and alpha-1 acid glycoprotein (AGP or orosomucoid) negated Imatinib's deleterious effects on adult S. mansoni and schistosomula (post-infective larvae) in vitro. This negative effect was partially reversed by erythromycin. AGP synthesis can increase as a consequence of inflammatory processes or infection; in addition upon infection AGP levels are 6-8 times higher in mice compared to humans. Therefore, mice and probably other rodents are poor infection models for measuring the effects of Imatinib in vivo. Accordingly, we suggest the routine evaluation of the ability of AGP and SA to block in vitro anti-schistosomal effects of small molecules like Imatinib prior to laborious and expensive animal experiments. (C) 2014 Published by Elsevier Ltd. on behalf of Australian Society for Parasitology Inc. This is an open access article under the CC BY-NC-ND license.
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