Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase

α-Difluoromethylornithine (DFMO), the specific and irreversible inhibitor of ornithine decarboxylase (ODC), was able to induce the arrest of proliferation in Leishmania mexicana and ODC-transformed Trypanosoma cruzi cultures grown in a semi-defined medium essentially free of polyamines. Conversely,...

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Autores principales: Carrillo, Carolina, Ceriani, María Carolina, González, Nélida Susana, Algranati, Israel David
Publicado: 2000
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Acceso en línea:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0006291X_v279_n2_p663_Carrillo
http://hdl.handle.net/20.500.12110/paper_0006291X_v279_n2_p663_Carrillo
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spelling paper:paper_0006291X_v279_n2_p663_Carrillo2023-06-08T14:30:12Z Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase Carrillo, Carolina Ceriani, María Carolina González, Nélida Susana Algranati, Israel David Crithidia fasciculata DFMO-resistance Leishmania mexicana Ornithine decarboxylase Phytomonas Polyamines Trypanosoma cruzi Trypanosomatids proliferation eflornithine ornithine decarboxylase spermidine trypanothione antiprotozoal activity article Crithidia fasciculata drug effect drug screening enzyme inhibition enzyme metabolism Leishmania mexicana nonhuman Phytomonas priority journal Trypanosoma cruzi α-Difluoromethylornithine (DFMO), the specific and irreversible inhibitor of ornithine decarboxylase (ODC), was able to induce the arrest of proliferation in Leishmania mexicana and ODC-transformed Trypanosoma cruzi cultures grown in a semi-defined medium essentially free of polyamines. Conversely, Crithidia fasciculata and Phytomonas 274 were not affected by the inhibitor. The drug-resistance of Crithidia and Phytomonas was neither caused by an impairment of DFMO uptake nor by a decrease of the enzyme affinity for the inhibitor. We were also able to rule out the possibility of ODC overexpression in the drug-tolerant parasites. The measurements of ODC metabolic turnover indicated that the enzymes from Crithidia and Phytomonas have a short half-life of 20-40 min, while ODC from Leishmania and transgenic Trypanosoma cruzi are rather stable with a half-life longer than 6 hours. Analyses of polyamine internal pools under different growth conditions have shown that DFMO was able to markedly decrease the levels of putrescine and spermidine in all parasites, but the depletion of spermidine was higher in trypanosomatids containing an ODC with slow turnover. Our results suggest that in these parasites cultivated in the presence of the drug, spermidine might decrease below critical levels needed to maintain trypanothione concentrations or other conditions essential for normal proliferation. © 2000 Academic Press. Fil:Carrillo, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Ceriani, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:González, N.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Algranati, I.D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2000 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0006291X_v279_n2_p663_Carrillo http://hdl.handle.net/20.500.12110/paper_0006291X_v279_n2_p663_Carrillo
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-134
collection Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic Crithidia fasciculata
DFMO-resistance
Leishmania mexicana
Ornithine decarboxylase
Phytomonas
Polyamines
Trypanosoma cruzi
Trypanosomatids proliferation
eflornithine
ornithine decarboxylase
spermidine
trypanothione
antiprotozoal activity
article
Crithidia fasciculata
drug effect
drug screening
enzyme inhibition
enzyme metabolism
Leishmania mexicana
nonhuman
Phytomonas
priority journal
Trypanosoma cruzi
spellingShingle Crithidia fasciculata
DFMO-resistance
Leishmania mexicana
Ornithine decarboxylase
Phytomonas
Polyamines
Trypanosoma cruzi
Trypanosomatids proliferation
eflornithine
ornithine decarboxylase
spermidine
trypanothione
antiprotozoal activity
article
Crithidia fasciculata
drug effect
drug screening
enzyme inhibition
enzyme metabolism
Leishmania mexicana
nonhuman
Phytomonas
priority journal
Trypanosoma cruzi
Carrillo, Carolina
Ceriani, María Carolina
González, Nélida Susana
Algranati, Israel David
Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase
topic_facet Crithidia fasciculata
DFMO-resistance
Leishmania mexicana
Ornithine decarboxylase
Phytomonas
Polyamines
Trypanosoma cruzi
Trypanosomatids proliferation
eflornithine
ornithine decarboxylase
spermidine
trypanothione
antiprotozoal activity
article
Crithidia fasciculata
drug effect
drug screening
enzyme inhibition
enzyme metabolism
Leishmania mexicana
nonhuman
Phytomonas
priority journal
Trypanosoma cruzi
description α-Difluoromethylornithine (DFMO), the specific and irreversible inhibitor of ornithine decarboxylase (ODC), was able to induce the arrest of proliferation in Leishmania mexicana and ODC-transformed Trypanosoma cruzi cultures grown in a semi-defined medium essentially free of polyamines. Conversely, Crithidia fasciculata and Phytomonas 274 were not affected by the inhibitor. The drug-resistance of Crithidia and Phytomonas was neither caused by an impairment of DFMO uptake nor by a decrease of the enzyme affinity for the inhibitor. We were also able to rule out the possibility of ODC overexpression in the drug-tolerant parasites. The measurements of ODC metabolic turnover indicated that the enzymes from Crithidia and Phytomonas have a short half-life of 20-40 min, while ODC from Leishmania and transgenic Trypanosoma cruzi are rather stable with a half-life longer than 6 hours. Analyses of polyamine internal pools under different growth conditions have shown that DFMO was able to markedly decrease the levels of putrescine and spermidine in all parasites, but the depletion of spermidine was higher in trypanosomatids containing an ODC with slow turnover. Our results suggest that in these parasites cultivated in the presence of the drug, spermidine might decrease below critical levels needed to maintain trypanothione concentrations or other conditions essential for normal proliferation. © 2000 Academic Press.
author Carrillo, Carolina
Ceriani, María Carolina
González, Nélida Susana
Algranati, Israel David
author_facet Carrillo, Carolina
Ceriani, María Carolina
González, Nélida Susana
Algranati, Israel David
author_sort Carrillo, Carolina
title Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase
title_short Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase
title_full Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase
title_fullStr Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase
title_full_unstemmed Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase
title_sort sensitivity of trypanosomatid protozoa to dfmo and metabolic turnover of ornithine decarboxylase
publishDate 2000
url https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0006291X_v279_n2_p663_Carrillo
http://hdl.handle.net/20.500.12110/paper_0006291X_v279_n2_p663_Carrillo
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