title: How Trypanosoma cruzi handles cell cycle arrest promoted by camptothecin, a topoisomerase I inhibitor.
abstract: The protozoan Trypanosoma cruzi is the etiological agent of Chagas disease, which affects approximately 8 million people in Latin America. This parasite contains a single nucleus and a kinetoplast, which harbors the mitochondrial DNA (kDNA). DNA topoisomerases act during replication, transcription and repair and modulate DNA topology by reverting supercoiling in the DNA double-strand. In this work, we evaluated the effects promoted by camptothecin, a topoisomerase I inhibitor that promotes protozoan proliferation impairment, cell cycle arrest, ultrastructure alterations and DNA lesions in epimastigotes of T. cruzi. The results showed that inhibition of cell proliferation was reversible only at the lowest drug concentration (1μM) used. The unpacking of nuclear heterochromatin and mitochondrion swelling were the main ultrastructural modifications observed. Inhibition of parasite proliferation also led to cell cycle arrest, which was most likely caused by nuclear DNA lesions. Following camptothecin treatment, some of the cells restored their DNA, whereas others entered early apoptosis but did not progress to late apoptosis, indicating that the protozoa stay alive in a "senescence-like" state. This programmed cell death may be associated with a decrease in mitochondrial membrane potential and an increase in the production of reactive oxygen species. Taken together, these results indicate that the inhibition of T. cruzi proliferation is related to events capable of affecting cell cycle, DNA organization and mitochondrial activity.
authors: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21491-590 Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Electronic address: alinezuma@ig.com.br.
authors: Aline Araujo
authors: AA
authors: Zuma
authors: Laboratório de Genética Bioquímica, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil.
authors: Isabela Cecília
authors: IC
authors: Mendes
authors: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21491-590 Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors: Lissa Catherine
authors: LC
authors: Reignault
authors: Laboratório Especial de Ciclo Celular, Instituto Butantan, Center of Toxins, Immune Response and Cell Signaling, 05503-900 São Paulo, SP, Brazil.
authors: Maria Carolina
authors: MC
authors: Elias
authors: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21491-590 Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Metrologia, Qualidade e Tecnologia-Inmetro, 20261-232 Duque de Caxias, RJ, Brazil.
authors: Wanderley
authors: W
authors: de Souza
authors: Laboratório de Genética Bioquímica, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil. Electronic address: crmachad@icb.ufmg.br.
authors: Carlos Renato
authors: CR
authors: Machado
authors: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21491-590 Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Electronic address: motta@biof.ufrj.br.
authors: Maria Cristina M
authors: MC
authors: Motta
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000166:cytology / Q000187:drug effects*
chemical_list: D059004:Topoisomerase I Inhibitors; D002166:Camptothecin
keywords: Apoptosis; Camptothecin; Cell cycle; Topoisomerase inhibitors; Trypanosoma cruzi; Ultrastructure