How Trypanosoma cruzi handles cell cycle arrest promoted by camptothecin, a topoisomerase I inhibitor

Zuma, Aline Araújo; Mendes, Isolda C.; Reignault, Lissa Catherine; Elias, Maria Carolina; Souza, Wanderley de; Machado, Carlos Renato; Motta, María Cristina M.

doi:10.1016/j.molbiopara.2014.02.001

Cited by 30 publications

(22 citation statements)

References 28 publications

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“…In agreement with microscopy analyses, our qPCR assays showed that berenil caused damage to the kDNA, but not the nuclear DNA, which can be affected after treatment with camptothecin (Zuma et al 2014). These data reinforce the idea that the kinetoplast is the main target of berenil (Macadam and Williamson 1972;Shapiro and Englund 1990).…”

Section: Resultssupporting

confidence: 88%

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Unveiling the effects of berenil, a DNA-binding drug, on Trypanosoma cruzi: implications for kDNA ultrastructure and replication

et al. 2014

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Section: Resultssupporting

confidence: 88%

“…This suggests that the prevention of mitochondrial DNA replication was not able to promote cell cycle blockade, as observed when nuclear DNA is affected by camptothecin, a topoisomerase I inhibitor that promotes heterochromatin unpacking (Zuma et al 2014).…”

Section: Resultsmentioning

confidence: 99%

Unveiling the effects of berenil, a DNA-binding drug, on Trypanosoma cruzi: implications for kDNA ultrastructure and replication

et al. 2014

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“…MB17 likely binds specifically to kinetoplast DNA, which results in the inhibition of DNA-dependent enzymes (10,11,31). Alternatively, MB17 may directly inhibit transcription and replication enzymes (11,31,(36)(37)(38). We propose that MB17 acts through its binding activity on the parasite DNA and not as a trypanocidal agent.…”

Section: Discussionmentioning

confidence: 91%

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

Girard

Crispim

Stolić

et al. 2016

Antimicrob Agents Chemother

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dTrypanosoma 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 M and an IC 50 of 0.14 ؎ 0.12 M against trypomastigote release. MB17 also diminished the infection index by 60% at 0.5 M. 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) (<90). These data suggest that MB17 could be an interesting lead compound against T. cruzi. A merican trypanosomiasis, or Chagas disease, affects approximately 10 million people, with 40 million people at risk of acquiring the infection. Chagas disease is endemic to South and Central America and the southern states of the United States. Currently, it is also spreading in Europe and the rest of North America due to the immigration of infected people, as well as through transmission of the disease by transfusions, transplants, and congenital mechanisms (1, 2). The disease is caused by the protozoan Trypanosoma cruzi, which shares some distinctive features with other trypanosomes, such as the presence of a flagellum and of a kinetoplast, a complex structure bearing the mitochondrial genome. In this case, the mitochondrial genomic DNA is referred to as kinetoplast DNA, or kDNA. It consists of a great number of relaxed circular DNA molecules interlocked with each other to form a catenated DNA network (3). T. cruzi has a complex life cycle, which occurs within invertebrate and vertebrate hosts (4-6). Chagas disease presents two clinical phases, the acute phase, which appears shortly after infection and is characterized by an evident parasitemia and ...

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“…For example, treatment with camptothecin caused cells in Trypanosoma cruzi to be arrested at an early stage instead of progressing to late apoptosis and cell death. Some studies have indicated that DNA repair can be activated in p53-induced apoptosis, leading to the reverse of apoptosis (Zuma et al 2014). Additionally, another explanation for this seeming contradiction concerns the deficiency of flow cytometry assays with Annexin V staining.…”

Section: Discussionmentioning

confidence: 99%

Aspirin-induced heat stress resistance in chicken myocardial cells can be suppressed by BAPTA-AM in vitro

Zhang

et al. 2016

Cell Stress and Chaperones

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Our recent studies have displayed the protective functions of aspirin against heat stress (HS) in chicken myocardial cells, and it may be associated with heat shock proteins (HSPs). In this study, we further investigated the potential role of HSPs in the aspirin-induced heat stress resistance. Four of the most important HSPs including HspB1 (Hsp27), Hsp60, Hsp70, and Hsp90 were induced by aspirin pretreatment and were suppressed by BAPTA-AM. When HSPs were induced by aspirin, much slighter HS injury was detected. But more serious damages were observed when HSPs were suppressed by BAPTA-AM than those cells exposed to HS without BAPTA-AM, even the myocardial cells have been treated with aspirin in prior. Comparing to other HSPs, HspB1 presented the largest increase after aspirin treatments, 86-fold higher than the baseline (the level before HS). These findings suggested that multiple HSPs participated in aspirin's anti-heat stress function but HspB1 may contribute the most. Interestingly, during the experiments, we also found that apoptosis rate as well as the oxidative stress indicators (T-SOD and MDA) was not consistently responding to heat stress injury as expected. By selecting from a series of candidates, myocardial cell damage-related enzymes (CK-MB and LDH), cytopathological tests, and necrosis rate (measured by flow cytometry assays) are believed to be reliable indicators to evaluate heat stress injury in chicken's myocardial cells and they will be used in our further investigations.

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How Trypanosoma cruzi handles cell cycle arrest promoted by camptothecin, a topoisomerase I inhibitor

Cited by 30 publications

References 28 publications

Unveiling the effects of berenil, a DNA-binding drug, on Trypanosoma cruzi: implications for kDNA ultrastructure and replication

Unveiling the effects of berenil, a DNA-binding drug, on Trypanosoma cruzi: implications for kDNA ultrastructure and replication

An Aromatic Diamidine That Targets Kinetoplast DNA, Impairs the Cell Cycle in Trypanosoma cruzi, and Diminishes Trypomastigote Release from Infected Mammalian Host Cells

Aspirin-induced heat stress resistance in chicken myocardial cells can be suppressed by BAPTA-AM in vitro

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