title: Serum albumin and α-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor Imatinib.
abstract: 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.
authors.affiliation: BFS, Institute for Parasitology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Beckmann
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and the Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Thavy
authors.initials: T
authors.lastname: Long
authors.affiliation: BFS, Institute for Parasitology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Scheld
authors.affiliation: Institute for Biochemistry, Justus-Liebig-University, Giessen, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Geyer
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases and the Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.affiliation: BFS, Institute for Parasitology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Christoph G
authors.initials: CG
authors.lastname: Grevelding
keywords: Abl tyrosine kinase (Abl); Erythromycin; Imatinib (Gleevec, Glivec, STI-571); In vitro culture; Protein tyrosine kinase (PTK); Schistosoma mansoni; Serum albumin (SA); α-1 acidic glycoprotein (AGP)