title: Plasmodium falciparum: the fungal metabolite gliotoxin inhibits proteasome proteolytic activity and exerts a plasmodicidal effect on P. falciparum.
abstract: The in vitro antimalarial activity of the fungal metabolite gliotoxin (GTX) was evaluated, and its mechanism of action was studied. GTX showed plasmodicidal activity against both Plasmodium falciparum chloroquine-resistant strain K-1 and chloroquine-susceptible strain FCR-3. GTX cytotoxicity was significantly lower against a normal liver cell line (Chang Liver cells). The intracellular reduced glutathione level of parasitized and of normal red blood cells was not affected by GTX treatment. However, GTX decreased the chymotrypsin-like activity of parasite proteasomes in a time-dependent manner. The results of this study indicate that GTX possesses plasmodicidal activity and that this effect is due to inhibition of parasite proteasome activity, suggesting that GTX may constitute a useful antimalarial therapy.
authors.affiliation: Gunma University School of Health Sciences, 3-39-15 Showa-machi, Maebashi, Gunma 371-8514, Japan. hatabu@health.gunma-u.ac.jp
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Hatabu
authors.forename: Masaki
authors.initials: M
authors.lastname: Hagiwara
authors.forename: Nao
authors.initials: N
authors.lastname: Taguchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kiyozawa
authors.forename: Mamoru
authors.initials: M
authors.lastname: Suzuki
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kano
authors.forename: Kumiko
authors.initials: K
authors.lastname: Sato
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D002918:Chymotrypsin / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects / Q000469:parasitology; D005912:Gliotoxin / Q000494:pharmacology* / Q000633:toxicity; D005978:Glutathione / Q000097:blood; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000166:cytology / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D005912:Gliotoxin; D002738:Chloroquine; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione