Voacamine alters Leishmania ultrastructure and kills parasite by poisoning unusual bi-subunit topoisomerase IB

Chowdhury, Somenath Roy; Kumar, Ashish; Godinho, Joseane Lima Prado; Silva, Sara Teixeira de Macedo; Zuma, Aline Araújo; Saha, Sourav; Kumari, Neha; Rodrigues, Juliany Cola Fernandes; Sundar, Shyam; Dujardin, Jean‐Claude; Roy, Syamal; Souza, Wanderley de; Mukhopadhyay, Sibabrata; Majumder, Hemanta K.

doi:10.1016/j.bcp.2017.05.002

Cited by 34 publications

(43 citation statements)

References 44 publications

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“…Isolation and maintenance of Leishmania amazonensis WHOM/BR/75/Josefa strain and Trypanosoma cruzi Y strain were done as reported previously 18 . In brief, amastigotes of L .…”

Section: Methodsmentioning

confidence: 99%

“…For T . cruzi , epimastigote forms were grown for 24 h at 28 °C in liver infusion tryptose 18 supplemented with 10% fetal calf serum. Promastigotes of Leishmania donovani WHOM/ET/1967/HU3 strain was kindly provided by the ‘ Leishmania Collection’ of the Instituto Oswaldo Cruz and cultivated with Schneider medium containing 10% of fetal bovine serum at 25 °C.…”

Section: Methodsmentioning

confidence: 99%

“…For transmission electron microscopy, cells were dehydrated in acetone and embedded in epoxy resin. Ultrathin sections were stained with uranyl acetate and lead citrate and observed under a Zeiss 900 electron microscope 16 , 18 . Several 2D thin sections were analyzed for each JVPH3 treatment group and untreated parasites.…”

Section: Methodsmentioning

confidence: 99%

“…There were around at least 15 to 20 cells in each section. For scanning electron microscopy, promastigotes were dehydrated in ethanol, critical point-dried in CO 2 , mounted on stubs, sputtered with a thin gold layer and observed under a FEI Quanta 250 scanning electron microscope 6 , 18 . At least 100 cells were observed for untreated and JVPH3 treated parasites.…”

Section: Methodsmentioning

confidence: 99%

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Isobenzofuranone derivative JVPH3, an inhibitor of L. donovani topoisomerase II, disrupts mitochondrial architecture in trypanosomatid parasites

Chowdhury

Godinho

Vinayagam

et al. 2018

Sci Rep

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Kinetoplast DNA (kDNA) bearing unusual mitochondrion of trypanosomatid parasites offers a new paradigm in chemotherapy modality. Topoisomerase II of Leishmania donovani (LdTopII), a key enzyme associated with kDNA replication, is emerging as a potential drug target. However, mode of action of LdTopII targeted compounds in the parasites at sub-cellular level remains largely unknown. Previously, we reported that an isobenzofuranone derivative, namely 3,5-bis(4-chlorophenyl)-7-hydroxyisobenzofuran-1(3H)-one (JVPH3), targets LdTopII and induces apoptosis-like cell death in L. donovani. Here, we elucidate the phenotypic changes and the events occurring at sub-cellular level caused by JVPH3 in L. donovani. In addition, we have evaluated the cytotoxicity and ultrastructural alterations caused by JVPH3 in two brazilian trypanosomatid pathogens viz. L. amazonensis and Trypanosoma cruzi. Despite killing these parasites, JVPH3 caused significantly different phenotypes in L. donovani and L. amazonensis. More than 90% population of parasites showed altered morphology. Mitochondrion was a major target organelle subsequently causing kinetoplast network disorganization in Leishmania. Altered mitochondrial architecture was evident in 75–80% Leishmania population being investigated. Quantification of mitochondrial function using JC-1 fluorophore to measure a possible mitochondrial membrane depolarization further confirmed the mitochondrion as an essential target of the JVPH3 corroborating with the phenotype observed by electron microscopy. However, the impact of JVPH3 was lesser on T. cruzi than Leishmania. The molecule caused mitochondrial alteration in 40% population of the epimastigotes being investigated. To our knowledge, this is the first report to evaluate the proliferation pattern and ultrastructural alterations caused in Brazilian kinetoplastid pathogens by a synthetic LdTopII inhibitor previously established to have promising in vivo activity against Indian strain of L. donovani.

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“…Isolation and maintenance of Leishmania amazonensis WHOM/BR/75/Josefa strain and Trypanosoma cruzi Y strain were done as reported previously 18 . In brief, amastigotes of L .…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Isobenzofuranone derivative JVPH3, an inhibitor of L. donovani topoisomerase II, disrupts mitochondrial architecture in trypanosomatid parasites

Chowdhury

Godinho

Vinayagam

et al. 2018

Sci Rep

Self Cite

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“…Recently, voacamine and an isobenzofuranone derivative induced important morphological alterations in different trypanosomatids, including T. cruzi. In Leishmania parasites, the most affected organelle was mitochondrion (severely swelled presenting membrane depolarization), where the derivative led to kinetoplast network disorganization [151,152].…”

Section: Nuclear and Kinetoplast Dnamentioning

confidence: 99%

Parasite, Compartments, and Molecules: Trick versus Treatment on Chagas Disease

Vannier‐Santos¹,

Brunoro²,

Soeiro³

et al. 2019

Biology OfTrypanosoma Cruzi

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Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic to Latin America, standing out as a socioeconomic problem for low-income tropical populations. Such disease affects millions of people worldwide and emerges in nonendemic areas due to migration and climate changes. The current chemotherapy is restricted to two nitroderivatives (benznidazole and nifurtimox), which is unsatisfactory due to limited efficacy (particularly in chronic phase) and adverse side effects. T. cruzi life cycle is complex, including invertebrate and vertebrate hosts and three developmental forms (epimastigotes, trypomastigotes, and amastigotes). In this chapter, we will discuss promising cellular and molecular targets present in the vertebrate-dwelling forms of the parasite (trypomastigotes and amastigotes). Among the cellular targets, the mitochondrion is the most frequently studied; while among the molecular ones, we highlight squalene synthase, C14α-sterol demethylase, and cysteine proteases. In this scenario, proteomics becomes a valuable tool for the identification of other molecular targets, and some previously identified candidates will be also discussed. Multidisciplinary studies are needed to identify novel key molecules in T. cruzi in order to increase trypanocidal activity and reduce mammalian toxicity, ensuring the development of novel drugs for Chagas disease.

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Stress‐responsive Entamoeba topoisomerase II: a potential antiamoebic target

Varghese

Ghosh

2019

FEBS Letters

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Topoisomerases, the ubiquitous enzymes involved in all DNA processes across the biological world, are targets for various anticancer and antimicrobial agents. In Entamoeba histolytica, the causative agent of amebiasis, we found one of seven unexplored putative topoisomerases to be highly upregulated during heat shock and oxidative stress, and also during the late hours of encystation. Further analysis revealed the upregulated enzyme to be a eukaryotic type IIA topoisomerase (TopoII) with demonstrable activity in vitro. This enzyme is localized to newly forming nuclei during encystation. Gene silencing of the TopoII reduces viability and encystation efficiency. Notable susceptibility of Entamoeba TopoII to prokaryotic topoisomerase inhibitors opens up the possibility for exploring this enzyme as a new antiamoebic target.

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Voacamine alters Leishmania ultrastructure and kills parasite by poisoning unusual bi-subunit topoisomerase IB

Cited by 34 publications

References 44 publications

Isobenzofuranone derivative JVPH3, an inhibitor of L. donovani topoisomerase II, disrupts mitochondrial architecture in trypanosomatid parasites

Isobenzofuranone derivative JVPH3, an inhibitor of L. donovani topoisomerase II, disrupts mitochondrial architecture in trypanosomatid parasites

Parasite, Compartments, and Molecules: Trick versus Treatment on Chagas Disease

Stress‐responsive Entamoeba topoisomerase II: a potential antiamoebic target

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