Effect of a β-lapachone-derived naphthoimidazole on Trypanosoma cruzi: identification of target organelles

Menna-Barreto, Rubem Figueiredo Sadok; Henriques-Pons, Andréa; Pinto, Antônio V.; Morgado‐Díaz, José Andrés; Soares, Maurílio J.; Castro, Solange L. de

doi:10.1093/jac/dki403

Cited by 89 publications

(100 citation statements)

References 27 publications

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“…127,128 Ultrastructural studies in epimastigotes and trypomastigotes treated with either one of three naphthoimidazoles N1, N2 and N3 derived from β-lapachone demonstrate that the mitochondrion, Golgi and reservosomes are the main targets. 128,129 Frequently, treatment with these three compounds induces morphological autophagic characteristics in the parasites such as the occurrence of concentric membrane structures in the cytosol and an increase in the number of autophagosome-like bodies, observations reinforced by the strong increase of monodansylcadaverine labeling. 130 The effect of the naphthoimidazoles on both forms of T. cruzi is blocked by E64 and calpain I inhibitor, 129 suggesting the participation of calpain in the autophagic process as in mammalian cells.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Autophagy in protists

et al. 2011

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Autophagy is the degradative process by which eukaryotic cells digest their own components using acid hydrolases within the lysosome. Originally thought to function almost exclusively in providing starving cells with nutrients taken from their own cellular constituents, autophagy is in fact involved in numerous cellular events including differentiation, turnover of macromolecules and organelles, and defense against parasitic invaders. During the last 10-20 years, molecular components of the autophagic machinery have been discovered, revealing a complex interactome of proteins and lipids, which, in a concerted way, induce membrane formation to engulf cellular material and target it for lysosomal degradation. Here, our emphasis is autophagy in protists. We discuss experimental and genomic data indicating that the canonical autophagy machinery characterized in animals and fungi appeared prior to the radiation of major eukaryotic lineages. Moreover, we describe how comparative bioinformatics revealed that this canonical machinery has been subject to moderation, outright loss or elaboration on multiple occasions in protist lineages, most probably as a consequence of diverse lifestyle adaptations. We also review experimental studies illustrating how several pathogenic protists either utilize autophagy mechanisms or manipulate host-cell autophagy in order to establish or maintain infection within a host. The essentiality of autophagy for the pathogenicity of many parasites, and the unique features of some of the autophagy-related proteins involved, suggest possible new targets for drug discovery. Further studies of the molecular details of autophagy in protists will undoubtedly enhance our understanding of the diversity and complexity of this cellular phenomenon and the opportunities it offers as a drug target

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Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Autophagy in protists

et al. 2011

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“…Naphthoimidazole N1, a -lapachone derivative, caused a decrease in the electron density of acidocalcisomes in T. cruzi trypomastigotes [55] (Fig. 2E).…”

Section: Acidocalcisomesmentioning

confidence: 97%

“…Looser kDNA organization is observed when parasites are incubated with naphtoquinones and naphthoimidazoles [55][56][57][58] (Fig. 2E).…”

Section: Kinetoplastmentioning

confidence: 97%

“…The mechanism of action of these compounds involves the generation of free radicals, which promote mitochondrial dysfunction. The effect of naphtoquinones and their naphthoimidazole derivatives on mitochondrion structure are drastic, with an intense swelling and the presence of intramitochondrial vesicles [54][55][56][57][58] (Figs. …”

Section: Mitochondriamentioning

confidence: 99%

“…Proanthocyanidin (an ethanolic extract from the Kola acuminata plant) seems to drastically increase the T. brucei rough ER content and the Golgi apparatus, which present up to seven to eight cristae [108]. In addition to inducing ER profiles surrounding cytoplasmic membrane structures, -lapachone derivatives also induced remarkable Golgi alterations, like disruption and enlargement of the trans-Golgi network cisternae [55,56]. Similarly, GG-OH treatment also caused effects on T. cruzi such as ER profiles surrounding organelles and myelin-like figures [72], suggesting an autophagic death pathway in response to both compounds.…”

Section: Endoplasmic Reticulum and Golgi Complexmentioning

confidence: 99%

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Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

Almeida¹,

Souto-Padrón

2010

TOPARAJ

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Protozoan parasites cause disease in humans worldwide, and many fall into the genera Trypanosoma and Leishmania; these parasites are responsible for African trypanosomiasis, Chagas disease and the different forms of Leishmaniasis. Strategies for the development of new drugs against these protozoans have been based on their cell biology and biochemistry complemented by the use of electron microscopy. Trypanosoma and Leishmania have special organelles that are involved in metabolic pathways, which are very distinct from those in mammalian cells; these organelles are potential drug targets. Scanning and transmission electron microscopy can identify not only the target organelles but also alterations to the cell surface and ultrastructural changes that characterize distinct forms of programmed cell death.

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Toxicological assessment of beta‐lapachone on organs from pregnant and non‐pregnant rats

Almeida

Lucena

Silva

et al. 2009

Phytotherapy Research

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Naphthoquinones have been studied extensively due to their activity as topoisomerase inhibitors. These enzymes are critical to DNA replication in cells. beta-Lapachone (beta-lap) is an o-naphthoquinone chemically obtained from lapachol. This work results in a toxicological evaluation of beta-lap in Wistar rats observing the following parameters: teratology, histology, hematology and serum biochemistry. The data demonstrate teratogenic action at the doses used, as well as hematological alterations in the total leukocytes, monocytes and segmented. The biochemical data demonstrated an increase in gamma glutamyl transferase, alkaline phosphatase and glutamate pyruvate transaminase levels. Histological study showed significant alterations in the spleen, however, the liver and kidney did not present significant alterations.

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Effect of a β-lapachone-derived naphthoimidazole on Trypanosoma cruzi: identification of target organelles

Cited by 89 publications

References 27 publications

Autophagy in protists

Autophagy in protists

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

Toxicological assessment of beta‐lapachone on organs from pregnant and non‐pregnant rats

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