An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells
Autor: | Miroslav Bajić, Flávia Silva Damasceno, Richard M. B. M. Girard, Elizabeth M. F. Pral, Marcell Crispim, Ariel Mariano Silber, Marcelo Santos da Silva, Ivana Stolić, Maria Carolina Elias |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Chagas disease DNA damage Trypanosoma cruzi CHO Cells Thiophenes Biology 03 medical and health sciences Cricetulus parasitic diseases medicine Cytotoxic T cell Animals Pharmacology (medical) Experimental Therapeutics Pentamidine Pharmacology Molecular Structure DNA Kinetoplast Cell Cycle Chemotherapy DNA/RNA binder kDNA cell cycle TRYPANOSOMA CRUZI Cell cycle medicine.disease biology.organism_classification Molecular biology Trypanocidal Agents Nuclear DNA Cell biology Benzamidines 030104 developmental biology Infectious Diseases Kinetoplast DNA fragmentation |
Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
Popis: | Trypanosoma cruzi is the etiological agent of Chagas disease, affecting approximately 10 million people in the Americas and with some 40 million people at risk. The objective of this study was to evaluate the anti- T. cruzi activity of three new diamidines that have a 3,4-ethylenedioxy extension of the thiophene core, designated MB17, MB19, and MB38. All three diamidines exhibited dose-dependent inhibition of epimastigote replication. The mechanisms of action of these diamidines were investigated. Unlike MB17 and MB19, MB38 exhibited a significant increase in the number of annexin-propidium iodide double-labeled cells compared to levels in control parasites. As MB17 had shown a lower 50% inhibitory concentration (IC 50 ) against epimastigote growth, the mechanism of action of this drug was studied in more detail. MB17 triggered a decrease in the intracellular ATP levels. As a consequence, MB17 affected the genomic DNA and kinetoplast DNA (kDNA) and impaired the parasite cell cycle. Moreover, MB17 caused DNA fragmentation, with a more severe effect on kDNA than on nuclear DNA, resulting in dyskinetoplastic cells. MB17 was tested for toxicity and effectiveness for the treatment of infected CHO-K 1 cells, exhibiting a 50% cytotoxic concentration (CC 50 ) of 13.47 ± 0.37 μM and an IC 50 of 0.14 ± 0.12 μM against trypomastigote release. MB17 also diminished the infection index by 60% at 0.5 μM. In conclusion, despite belonging to the same family, these diamidines have different efficiencies. To summarize, MB17 was the most potent of these diamidines against epimastigotes, producing DNA damage preferentially in kDNA, impairing the parasite cell cycle, and decreasing the infection index and trypomastigote release from infected mammalian host cells, with a high selectivity index (SI) (T. cruzi . |
Databáze: | OpenAIRE |
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