Effect of a new anti-T. cruzi metallic compound based on palladium

Mosquillo, M. Florencia; Bilbao, Lucía; Hernández, Fabricio; Machado, Ignacio; Gambino, Dinorah; Garat, Beatríz; Pérez-Díaz, Leticia

doi:10.1007/s10534-018-0140-4

Cited by 16 publications

(12 citation statements)

References 28 publications

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“…ough the percentage of the compound uptaken by the parasites (less than 2.4% of the total vanadium used for incubation) is similar to that obtained for other well-known metallic antiproliferative compounds such as cisplatin (3%), oxaliplatin (1%), or pyrodach-2 (0.1%) in three different human cell lines [39], it is notably lower than the ones obtained for other metal-based compounds (more than 20%) in T. cruzi epimastigotes [25,26]. Nonetheless, the low V IV O(5Brsal)(aminophen) uptake is enough to exert the antiparasitic effect.…”

Section: Discussionsupporting

confidence: 80%

“…e aim of this work was to evaluate the cellular and molecular mechanism of action of a new vanadium-based compound in T. cruzi. Proliferation assays revealed an IC 50 value of (3.76 ± 0.08) μM, similar to the one of the reference drug nifurtimox, (2.8 ± 0.2) μM [25,26]. us, V IV O(5Brsal)(aminophen) can be visualized as a promising antiproliferative compound.…”

Section: Discussionmentioning

confidence: 59%

“…Activity. Anti-T. cruzi activity was determined following a previously reported method [25][26][27]. Briefly, an 11.25 mM V IV O(5Brsal)(aminophen) solution was prepared in dimethyl sulfoxide (DMSO).…”

Section: Determination Of In Vitro Anti-trypanosoma Cruzimentioning

confidence: 99%

“…Recovery assays of T. cruzi epimastigotes were performed as previously described [25,28]. Epimastigotes were incubated for 4 h with 1x, 5x, and 10x IC 50 of V IV O(5Brsal)(aminophen) and washed with and transferred to fresh compound-free BHI.…”

Section: Recovery Assaysmentioning

confidence: 99%

“…To find out if cell death mechanisms such as early apoptosis or necrosis/late apoptosis were involved, we performed flow cytometry analysis with the fluorescent hallmark probes AV and PI as described previously [25][26][27]. e absence of AV and/or PI positive cells after incubation with either 1x, 5x, or 10x IC 50 for 24 h suggests that neither apoptosis nor necrosis processes were triggered by the V IV O(5Brsal)(aminophen) treatment (Figure 3(a)).…”

Section: Growth Inhibition Mechanisms Of V Iv O(5brsal)-(aminophen) Imentioning

confidence: 99%

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High Throughput Approaches to Unravel the Mechanism of Action of a New Vanadium-Based Compound against Trypanosoma cruzi

Mosquillo

Smircich

Lima

et al. 2020

Bioinorganic Chemistry and Applications

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Treatment for Chagas disease, a parasitosis caused by Trypanosoma cruzi, has always been based on two drugs, nifurtimox and benznidazole, despite the toxic side effects described after prolonged prescription. In this work, we study a new prospective antitrypanosomal drug based on vanadium, here named V IV O(5Brsal)(aminophen). We found a good IC 50 value, (3.76 ± 0.08) μM, on CL Brener epimastigotes. e analysis of cell death mechanism allowed us to rule out the implication of a mechanism based on early apoptosis or necrosis. Recovery assays revealed a trypanostatic effect, accompanied by cell shape and motility alterations. An uptake mostly associated with the insoluble fraction of the parasites was deduced through vanadium determinations. Concordantly, no drastic changes of the parasite transcriptome were detected after 6 h of treatment. Instead, proteomic analysis uncovered the modulation of proteins involved in different processes such as energy and redox metabolism, transport systems, detoxifying pathways, ribosomal protein synthesis, and proteasome protein degradation. Overall, the results here presented lead us to propose that V IV O(5Brsal)(aminophen) exerts a trypanostatic effect on T. cruzi affecting parasite insoluble proteins.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 59%

Section: Determination Of In Vitro Anti-trypanosoma Cruzimentioning

confidence: 99%

Section: Recovery Assaysmentioning

confidence: 99%

Section: Growth Inhibition Mechanisms Of V Iv O(5brsal)-(aminophen) Imentioning

confidence: 99%

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High Throughput Approaches to Unravel the Mechanism of Action of a New Vanadium-Based Compound against Trypanosoma cruzi

Mosquillo

Smircich

Lima

et al. 2020

Bioinorganic Chemistry and Applications

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Platinum and Palladium Organometallic Compounds: Disrupting the Ergosterol Pathway in Trypanosoma cruzi

et al. 2023

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Current treatment for Chagas’ disease is based on two drugs, Nifurtimox and Benznidazol, which have limitations that reduce the effectiveness and continuity of treatment. Thus, there is an urgent need to develop new, safe and effective drugs. In previous work, two new metal‐based compounds with trypanocidal activity, Pd‐dppf‐mpo and Pt‐dppf‐mpo, were fully characterized. To unravel the mechanism of action of these two analogous metal‐based drugs, high‐throughput omics studies were performed. A multimodal mechanism of action was postulated with several candidates as molecular targets. In this work, we validated the ergosterol biosynthesis pathway as a target for these compounds through the determination of sterol levels by HPLC in treated parasites. To understand the molecular level at which these compounds participate, two enzymes that met eligibility criteria at different levels were selected for further studies: phosphomevalonate kinase (PMK) and lanosterol 14‐α demethylase (CYP51). Molecular docking processes were carried out to search for potential sites of interaction for both enzymes. To validate these candidates, a gain‐of‐function strategy was used through the generation of overexpressing PMK and CYP51 parasites. Results here presented confirm that the mechanism of action of Pd‐dppf‐mpo and Pt‐dppf‐mpo compounds involves the inhibition of both enzymes.

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Structural investigation of group 10 metal complexes with thiosemicarbazone: crystal structure, mass spectrometry, Hirshfeld surface and in vitro antitumor activity

et al. 2020

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Effect of a new anti-T. cruzi metallic compound based on palladium

Cited by 16 publications

References 28 publications

High Throughput Approaches to Unravel the Mechanism of Action of a New Vanadium-Based Compound against Trypanosoma cruzi

High Throughput Approaches to Unravel the Mechanism of Action of a New Vanadium-Based Compound against Trypanosoma cruzi

Platinum and Palladium Organometallic Compounds: Disrupting the Ergosterol Pathway in Trypanosoma cruzi

Structural investigation of group 10 metal complexes with thiosemicarbazone: crystal structure, mass spectrometry, Hirshfeld surface and in vitro antitumor activity

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