Effect of protein kinase inhibitors on the growth, morphology, and infectivity of Leishmania promastigotes.
The effect of two protein kinase inhibitors, staurosporine and H-7, on the growth, morphology and infectivity of Leishmania major and Leishmania amazonensis promastigotes was examined. Incubation with H-7 (600 microM) for up to one hour had no effect on parasite growth, morphology or infectivity. Staurosporine, however, was cytotoxic for promastigotes and incubation for 1, 5 or 15 minutes with 10 microM inhibitor killed 19, 34 and 59%, respectively, of the parasites. Longer incubations, up to one hour, at this concentration did not increase parasite killing. However, treatment with 25 microM staurosporine for one hour was highly toxic, only 4% of the promastigotes surviving after 72 h. Lower concentrations of staurosporine, 0.25 and 2.5 microM, had only minor effects on parasite growth. Incubation of either L. major or L. amazonensis with staurosporine (10 microM for 10 minutes) caused marked morphological changes in the size and appearance of the flagellar pocket, and/or cytoplasm of the viable parasites. Treated parasites were still capable of infecting mouse peritoneal macrophages and causing disease in BALB/c mice, though the treated parasites were less virulent than control promastigotes. These results indicate that staurosporine, while inhibiting promastigote growth, does not prevent differentiation to amastigotes and amastigote replication.
Becker
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Department of Parasitology, Kuvin Center for Tropical and Infectious Diseases, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Jaffe
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity / Q000648:ultrastructure; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity / Q000648:ultrastructure; D007896:Leishmaniasis / Q000503:physiopathology; D016773:Leishmaniasis, Cutaneous / Q000503:physiopathology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015800:Protozoan Proteins / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine