Pentamidine exerts in vitro and in vivo anti Trypanosoma cruzi activity and inhibits the polyamine transport in Trypanosoma cruzi

Díaz, María V.; Miranda, Mariana R.; Campos‐Estrada, Carolina; Reigada, Chantal; Maya, Juan Diego; Pereira, Claudio A.; López‐Muñoz, Rodrigo

doi:10.1016/j.actatropica.2014.02.012

Cited by 33 publications

(37 citation statements)

References 54 publications

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“…At very low concentrations, isotretinoin inhibited the trypomastigotes burst after six days of infection, with a calculated IC 50 of 130 nM (Fig 4B). Remarkably, this IC 50 value is significantly lower than those obtained for the drugs currently used as a treatment for Chagas disease [12,16]. The calculated selectivity index of isotretinoin against trypomastigotes over human macrophages was about 920.…”

Section: Resultsmentioning

confidence: 88%

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Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

et al. 2017

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Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6–10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 μM). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.

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Section: Resultsmentioning

confidence: 88%

“…cruzi . Recent studies have shown that the trypanocidal drug pentamidine blocks Tc PAT12 in this parasite [16,17]. All this evidence highlights that T .…”

Section: Introductionmentioning

confidence: 94%

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

et al. 2017

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“…T . cruzi lacks the enzymes l-arginine decarboxylase and ornithine decarboxylase, required to synthesize putrescine de novo , and incorporates the polyamine from the medium through the polyamine transporter TcPAT12, which is blocked by pentamidine [40]. Artemisinin, a sesquiterpene trioxan lactone derived from Artemisia annua , and its derivatives are widely used against P .…”

Section: Discussionmentioning

confidence: 99%

Phenotypic diversity and drug susceptibility of Trypanosoma cruzi TcV clinical isolates

et al. 2018

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Trypanosoma cruzi is a genetically heterogeneous group of organisms that cause Chagas disease. It has been long suspected that the clinical outcome of the disease and response to therapeutic agents are, at least in part, related to the genetic characteristics of the parasite. Herein, we sought to validate the significance of the genotype of T. cruzi isolates recovered from patients with different clinical forms of Chagas disease living in Argentina on their biological behaviour and susceptibility to drugs. Genotype identification of the newly established isolates confirmed the reported predominance of TcV, with a minor frequency of TcI. Epimastigote sensitivity assays demonstrated marked dissimilar responses to benznidazole, nifurtimox, pentamidine and dihydroartemisinin in vitro. Two TcV isolates exhibiting divergent response to benznidazole in epimastigote assays were further tested for the expression of anti-oxidant proteins. Benznidazole-resistant BOL-FC10A epimastigotes had decreased expression of Old Yellow Enzyme and cytosolic superoxide dismutase, and overexpression of mitochondrial superoxide dismutase and tryparedoxin- 1, compared to benznidazole-susceptible AR-SE23C parasites. Drug sensitivity assays on intracellular amastigotes and trypomastigotes reproduced the higher susceptibility of AR-SE23C over BOL-FC10A parasites to benznidazole observed in epimastigotes assays. However, the susceptibility/resistance profile of amastigotes and trypomastigotes to nifurtimox, pentamidine and dihydroartemisinin varied markedly with respect to that of epimastigotes. C3H/He mice infected with AR-SE23C trypomastigotes had higher levels of parasitemia and mortality rate during the acute phase of infection compared to mice infected with BOL-FC10A trypomastigotes. Treatment of infected mice with benznidazole or nifurtimox was efficient to reduce patent parasitemia induced by either isolate. Nevertheless, qPCR performed at 70 dpi revealed parasite DNA in the blood of mice infected with AR-SE23C but not in BOL-FC10A infected mice. These results demonstrate high level of intra-type diversity which may represent an important obstacle for the testing of chemotherapeutic agents.

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“…Nevertheless it may furnish significant insights for the infection chemotherapy, as β-lapachone was reported to produce similar alterations in T. cruzi epimastigotes, amastigotes and trypomastigotes (Docampo et al., 1978), the developmental forms that multiply within mammalian host cells and spread via blood, respectively. In addition, different antiparasitic compounds may display similar effects upon epimastigotes and trypomastigotes and/or amastigotes, the developmental forms (Urbina et al., 1988, Urbina et al., 1993; Moreira et al., 2013a; Costa et al., 2011, Azeredo et al., 2014, Díaz et al., 2014; Jimenez et al., 2014; Veiga-Santos et al., 2014, Britta et al., 2015, Meira et al., 2015, Volpato et al., 2015, Beer et al., 2016) and the epimastigotes may therefore comprise and/or take part in experimental models (Kessler et al., 2013, Benítez et al., 2014, Sangenito et al., 2014, Wong-Baeza et al., 2015, Khare et al., 2015, Pessoa et al., 2016, Valera Vera et al., 2016). Thus, numerous studies perform screening experiments with epimastigotes and/or trypomastigotes further approach the selected active compounds in intracellular amastigotes (e.g.…”

Section: Discussionmentioning

confidence: 99%

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

Anjos

Alves

Goncalves

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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Natural products comprise valuable sources for new antiparasitic drugs. Here we tested the effects of a novel β–lapachone derivative on Trypanosoma cruzi parasite survival and proliferation and used microscopy and cytometry techniques to approach the mechanism(s) underlying parasite death. The selectivity index determination indicate that the compound trypanocidal activity was over ten-fold more cytotoxic to epimastigotes than to macrophages or splenocytes. Scanning electron microscopy analysis revealed that the R72 β–lapachone derivative affected the T. cruzi morphology and surface topography. General plasma membrane waving and blebbing particularly on the cytostome region were observed in the R72-treated parasites. Transmission electron microscopy observations confirmed the surface damage at the cytostome opening vicinity. We also observed ultrastructural evidence of the autophagic mechanism termed macroautophagy. Some of the autophagosomes involved large portions of the parasite cytoplasm and their fusion/confluence may lead to necrotic parasite death. The remarkably enhanced frequency of autophagy triggering was confirmed by quantitating monodansylcadaverine labeling. Some cells displayed evidence of chromatin pycnosis and nuclear fragmentation were detected. This latter phenomenon was also indicated by DAPI staining of R72-treated cells. The apoptotis induction was suggested to take place in circa one-third of the parasites assessed by annexin V labeling measured by flow cytometry. TUNEL staining corroborated the apoptosis induction. Propidium iodide labeling indicate that at least 10% of the R72-treated parasites suffered necrosis within 24 h. The present data indicate that the β–lapachone derivative R72 selectively triggers T. cruzi cell death, involving both apoptosis and autophagy-induced necrosis.

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Pentamidine exerts in vitro and in vivo anti Trypanosoma cruzi activity and inhibits the polyamine transport in Trypanosoma cruzi

Cited by 33 publications

References 54 publications

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi

Phenotypic diversity and drug susceptibility of Trypanosoma cruzi TcV clinical isolates

Effects of a novel β–lapachone derivative on Trypanosoma cruzi : Parasite death involving apoptosis, autophagy and necrosis

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