In vitro effects of new artemisinin derivatives in Neospora caninum-infected human fibroblasts.
From a panel of 34 artemisinin derivatives tested in vitro, artemisone, GC007 and GC012 were most efficacious at inhibiting Neospora caninum replication (IC50 values of 3-54nM), did not notably impair the invasiveness of tachyzoites and were non-toxic for human foreskin fibroblasts (HFFs). Transmission electron microscopy of drug-treated N. caninum-infected HFFs demonstrated severe alterations in the parasite cytoplasm, changes in the composition of the matrix of the parasitophorous vacuole (PV) and diminished integrity of the PV membrane. To exert parasiticidal activity, parasites had to be cultured continuously in the presence of 5μM artemisone or GC007 for 3 weeks. N. caninum tachyzoites readily adapted to a stepwise increase in concentrations (0.5-10μM) of GC012, but not to artemisone or GC007. Drugs induced the expression of elevated levels of NcBAG1 and NcSAG4 mRNA, but only NcBAG1 could be detected by immunofluorescence. Thus, artemisinin derivatives represent interesting leads that should be investigated further.
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Joachim
J
Müller
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Vreni
V
Balmer
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Pablo
P
Winzer
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Mahbubur
M
Rahman
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland.
Vera
V
Manser
Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences G2, North-West University Potchefstroom Campus, 11 Hoffman Street, Potchefstroom 2531, South Africa.
Richard K
RK
Haynes
Institute of Parasitology, Vetsuisse Faculty, University of Berne, Länggass-Strasse 122, CH-3012 Berne, Switzerland. Electronic address: andrew.hemphill@vetsuisse.unibe.ch.
Andrew
A
Hemphill
D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000633:toxicity; D037621:Artemisinins / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D058492:Drug Repositioning; D004361:Drug Tolerance; D005347:Fibroblasts / Q000187:drug effects* / Q000469:parasitology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000494:pharmacology* / Q000633:toxicity; D046529:Microscopy, Electron, Transmission; D018688:Neospora / Q000187:drug effects* / Q000648:ultrastructure; D021261:Parasitic Sensitivity Tests
D000981:Antiprotozoal Agents; D037621:Artemisinins; D007783:Lactones; C075875:artemisin
Artemisinin; Artemisone; Chemotherapy; Neospora caninum; Resistance; Trioxolane