Plasmodium falciparum: the fungal metabolite gliotoxin inhibits proteasome proteolytic activity and exerts a plasmodicidal effect on P. falciparum.
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.
Hatabu
Toshimitsu
T
Gunma University School of Health Sciences, 3-39-15 Showa-machi, Maebashi, Gunma 371-8514, Japan. hatabu@health.gunma-u.ac.jp
Hagiwara
Masaki
M
Taguchi
Nao
N
Kiyozawa
Masayuki
M
Suzuki
Mamoru
M
Kano
Shigeyuki
S
Sato
Kumiko
K
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
D000962:Antimalarials; D005912:Gliotoxin; D002738:Chloroquine; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione