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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todo:paper_0006291X_v279_n2_p663_Carrillo2023-10-03T14:03:47Z Sensitivity of trypanosomatid protozoa to DFMO and metabolic turnover of ornithine decarboxylase Carrillo, C. Cejas, S. Cortés, M. Ceriani, C. Huber, A. González, N.S. Algranati, I.D. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar 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, C. Cejas, S. Cortés, M. Ceriani, C. Huber, A. González, N.S. Algranati, I.D. 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. |
| format |
JOUR |
| author |
Carrillo, C. Cejas, S. Cortés, M. Ceriani, C. Huber, A. González, N.S. Algranati, I.D. |
| author_facet |
Carrillo, C. Cejas, S. Cortés, M. Ceriani, C. Huber, A. González, N.S. Algranati, I.D. |
| author_sort |
Carrillo, C. |
| 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 |
| url |
http://hdl.handle.net/20.500.12110/paper_0006291X_v279_n2_p663_Carrillo |
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