Pentamidine antagonizes the benznidazole's effect in vitro, and lacks of synergy in vivo: Implications about the polyamine transport as an anti-Trypanosoma cruzi target

Seguel, Verónica; Castro, Lorena; Reigada, Chantal; Cortes, Leonel A.; Díaz, María V.; Miranda, Mariana R.; Pereira, Claudio A.; Lapier, Michel; Campos‐Estrada, Carolina; Morello, Antonio; Kemmerling, Ulrike; Maya, Juan Diego; López‐Muñoz, Rodrigo

doi:10.1016/j.exppara.2016.10.007

Cited by 13 publications

(5 citation statements)

References 34 publications

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“…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: 93%

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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“…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: 93%

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

et al. 2017

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“…To study the effect of the simultaneous or sequential combination of IVM with BZN or NFX, epimastigotes were cultured in combination matrices and the obtained data were analyzed with the free software Combenefit ( Di Veroli et al., 2016 ), in which the null hypothesis of no synergy needs to be defined in order to assess the degree of the effect. In the case of IVM+BZN and IVM+NFX, the hypothesis was that these drugs have different mechanisms of action, taking the Bliss independence model as the best approach ( Seguel et al., 2016 ; Tang, 2017 ). When the drugs were combined simultaneously, synergy distribution heatmaps-obtained from the comparison of experimental data with model-predicted values-showed an additive behavior in most of the concentrations.…”

Section: Resultsmentioning

confidence: 99%

Broadening the spectrum of ivermectin: Its effect on Trypanosoma cruzi and related trypanosomatids

Fraccaroli

Ruiz

Perdomo

et al. 2022

Front. Cell. Infect. Microbiol.

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Chagas disease is an endemic American parasitosis, caused by Trypanosoma cruzi. The current therapies, benznidazole (BZN) and nifurtimox (NFX), show limited efficacy and multiple side effects. Thus, there is a need to develop new trypanocidal strategies. Ivermectin (IVM) is a broad-spectrum antiparasitic drug with low human and veterinary toxicity with effects against T. brucei and Leishmania spp. Considering this and its relatively low cost, we evaluate IVM as a potential repurposed trypanocidal drug on T. cruzi and other trypanosomatids. We found that IVM affected, in a dose-dependent manner, the proliferation of T. cruzi epimastigotes as well as the amastigotes and trypomastigotes survival. The Selectivity Index for the amastigote stage with respect to Vero cells was 12. The IVM effect was also observed in Phytomonas jma 066 and Leishmania mexicana proliferation but not in Crithidia fasciculata. On the epimastigote stage, the IVM effect was trypanostatic at 50 μM but trypanocidal at 100 μM. The assays of the drug combinations of IVM with BNZ or NFX showed mainly additive effects among combinations. In silico studies showed that classical structures belonging to glutamate-gated Cl channels, the most common IVM target, are absent in kinetoplastids. However, we found in the studied trypanosomatid genomes one copy for putative IMPα and IMPβ, potential targets for IVM. The putative IMPα genes (with 76% similarity) showed conserved Armadillo domains but lacked the canonical IMPβ binding sequence. These results allowed us to propose a novel molecular target in T. cruzi and suggest IVM as a good candidate for drug repurposing in the Chagas disease context.

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“…With that inspiration, we selected 32 commercial drugs and tested them for their anti-T. cruzi activity. Seven showed high activity against the parasite, and according to the literature only four of them had been previously evaluated against T. cruzi: nifedipine [27], verapamil [46][47][48][49], pentamidine [50,51] and miltefosine [39][40][41][42]. After assessing host cell toxicity over Vero cells, lidocaine and nifedipine were discarded because they returned a higher toxicity rate than the rest.…”

Section: Discussionmentioning

confidence: 99%

“…Even though it was active and specific against T. cruzi, we discarded pentamidine given its history of severely toxic side effects upon parenteral inoculation [65,66]. Moreover, the lack of synergy between BNZ and pentamidine in an in vivo model of T. cruzi infection has been reported [51], and it was previously observed that it had lower activity than BNZ [50]. Thus, we decided to test in vivo the same three drugs that went to the anti-amastigote assay.…”

Section: Discussionmentioning

confidence: 99%

Identification of Trypanosoma cruzi Growth Inhibitors with Activity In Vivo within a Collection of Licensed Drugs

et al. 2021

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Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), affects more than six million people worldwide, with its greatest burden in Latin America. Available treatments present frequent toxicity and variable efficacy at the chronic phase of the infection, when the disease is usually diagnosed. Hence, development of new therapeutic strategies is urgent. Repositioning of licensed drugs stands as an attractive fast-track low-cost approach for the identification of safer and more effective chemotherapies. With this purpose we screened 32 licensed drugs for different indications against T. cruzi. We used a primary in vitro assay of Vero cells infection by T. cruzi. Five drugs showed potent activity rates against it (IC50 < 4 µmol L−1), which were also specific (selectivity index > 15) with respect to host cells. T. cruzi inhibitory activity of four of them was confirmed by a secondary anti-parasitic assay based on NIH-3T3 cells. Then, we assessed toxicity to human HepG2 cells and anti-amastigote specific activity of those drugs progressed. Ultimately, atovaquone-proguanil, miltefosine, and verapamil were tested in a mouse model of acute T. cruzi infection. Miltefosine performance in vitro and in vivo encourages further investigating its use against T. cruzi.

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Pentamidine antagonizes the benznidazole's effect in vitro, and lacks of synergy in vivo: Implications about the polyamine transport as an anti-Trypanosoma cruzi target

Cited by 13 publications

References 34 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

Broadening the spectrum of ivermectin: Its effect on Trypanosoma cruzi and related trypanosomatids

Identification of Trypanosoma cruzi Growth Inhibitors with Activity In Vivo within a Collection of Licensed Drugs

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