Apoptotic Death in Leishmania donovani Promastigotes in Response to Respiratory Chain Inhibition

Mehta, Ashish; Shaha, Chandrima

doi:10.1074/jbc.m309341200

Cited by 174 publications

(125 citation statements)

References 51 publications

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“…The generation of excessive reactive oxygen species is seen as an important factor in apoptosis. Therefore, it is interesting to note that similar effects have been observed following exposure to hydrogen peroxide (46) or to reactive oxygen species generated as a result of inhibition of electron transport (47). Leishmania lack catalase and metabolize hydrogen peroxide through trypanothione-dependent peroxidases, so they are unusually reliant on a functioning trypanothione system for defense against oxidative stress.…”

Section: T[sh] 2 Coupled With Inhibition Of Gsh and T[sh] 2 Biosynthementioning

confidence: 94%

Dual Action of Antimonial Drugs on Thiol Redox Metabolism in the Human Pathogen Leishmania donovani

Wyllie

Cunningham

Fairlamb

2004

Journal of Biological Chemistry

266

247

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Despite extensive use of antimonial compounds in the treatment of leishmaniasis, their mode of action remains uncertain. Here we show that trivalent antimony (Sb III ) interferes with trypanothione metabolism in drug-sensitive Leishmania parasites by two inherently distinct mechanisms. First, Sb III decreases thiol buffering capacity by inducing rapid efflux of intracellular trypanothione and glutathione in approximately equimolar amounts. Second, Sb III inhibits trypanothione reductase in intact cells resulting in accumulation of the disulfide forms of trypanothione and glutathione. These two mechanisms combine to profoundly compromise the thiol redox potential in both amastigote and promastigote stages of the life cycle. Furthermore, we demonstrate that sodium stibogluconate, a pentavalent antimonial used clinically for the treatment for leishmaniasis, induces similar effects on thiol redox metabolism in axenically cultured amastigotes. These observations suggest ways in which current antimony therapies could be improved, overcoming the growing problem of antimony resistance.Leishmania parasites cause a wide spectrum of human and animal infections ranging from life-threatening visceral disease to disfiguring mucosal and cutaneous forms of the disease. These "neglected" diseases are a significant cause of morbidity and mortality in 88 countries in the Americas, Africa, Asia, and Southern Europe; millions of people are at risk, and 400,000 new cases are reported annually (1). Leishmania spp. are obligate intracellular parasites of the vertebrate reticuloendothelial system, where they multiply as amastigotes in macrophage phagolysosomes; transmission is by blood-sucking sandflies, in which they proliferate as extracellular promastigotes. Treatment of the leishmaniases is far from ideal, and pentavalent antimonial (Sb V ) 1 preparations such as sodium stibogluconate (Pentostam) have been the front-line drugs for more than half a century. However, the clinical value of antimony therapy is now threatened because of the emergence of drug resistance (2) and co-infection with human immunodeficiency virus (3). Sb V is generally regarded as a pro-drug that first has to be activated by conversion to the trivalent form (Sb III ) (4). However, the site of reduction (host macrophage, amastigote, or both) and the mechanism of reduction (enzymatic or nonenzymatic) remain unclear (4 -8). The mode of action of these drugs is poorly understood. Sb III reversibly inhibits trypanothione reductase in vitro (9), but this has not been demonstrated in the intact parasite. However, inhibition of this unique and essential enzyme (10 -12) is of particular interest, because trypanothione (N 1 ,N 8Ϫ bis(glutathionyl) spermidine (T[SH] 2 )) is a key intermediate in the regulation of thiol redox homeostasis, as well as in defense against chemical (13,14) and oxidative stress (15, 16).Paradoxically, more is known about the mechanism of resistance to Sb III than its mode of action (17). A considerable body of evidence implicates trypanothione a...

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Section: T[sh] 2 Coupled With Inhibition Of Gsh and T[sh] 2 Biosynthementioning

confidence: 94%

Dual Action of Antimonial Drugs on Thiol Redox Metabolism in the Human Pathogen Leishmania donovani

Wyllie

Cunningham

Fairlamb

2004

Journal of Biological Chemistry

266

247

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“…Retinoids can trans-regulate a number of signaling pathways, such as AP-1, in diverse cell types (Altucci and Gronemeyer, 2001;Mehta, 2003), and AP-1, signaling is inhibited by RA in wild-type, but not RAR-null, keratinocytes. This effect is recovered in the latter after the reintroduction of RARa, and correlates with resistance to Ras-induced tumorigenesis.…”

Section: Roles Of Rarc In Epithelial Tumorigenesis Cf Chen Et Almentioning

confidence: 99%

“…In addition to direct regulation of target genes, RARs, like several other nuclear receptors, can impact on gene expression by trans-repression of other transcription factors, such as activating protein 1 (AP-1) (Altucci and Gronemeyer, 2001;Mehta, 2003). AP-1 activity has been closely linked to epidermal tumorigenesis in vivo and cellular transformation in vitro (Jochum et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

RARγ acts as a tumor suppressor in mouse keratinocytes

2004

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All-trans retinoic acid (RA), the principal biologically active form of vitamin A, is essential for many developmental process as well as homeostasis in the adult. Many lines of evidence also suggest that RA, acting through the RA receptors (RARs), can also suppress growth of tumors of diverse origin. To assess directly the role of the RARs in a model of epidermal tumorigenesis, we investigated the incidence of tumor formation using keratinocytes lacking specific RAR types. Our data suggest that loss of RARc, but not RARa, predisposed keratinocytes to v-Ha-Rasinduced squamous cell carcinoma. We also found that ablation of RARc, but not RARa, abolished RA-induced cell cycle arrest and apoptosis in these keratinocytes. Reconstitution of receptor expression into RAR-null cells restored sensitivity to RA, and reversed the tumorigenic potential of receptor-deficient keratinocytes. These data strongly support a tumor suppressor effect for the RARs, in particular endogenous RARc, in murine keratinocytes.

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“…In metazoan and unicellular cells, translocation of PS from the inner to the outer leaflet of the plasma membrane occurs during programmed cell death (PCD) (Mehta & Shaha, 2004;Sudhandiran & Shaha, 2003;Koonin & Aravind, 2002). Annexin V, a Ca 2+ -dependent phospholipid-binding protein with affinity for PS, is used routinely to label its externalization.…”

Section: Externalization Of Ps In Promastigotesmentioning

confidence: 99%

Extracts of Artemisia annua leaves and seeds mediate programmed cell death in Leishmania donovani

Islamuddin

Farooque

Dwarakanath

et al. 2012

Journal of Medical Microbiology

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Leishmaniasis is one of the major tropical parasitic diseases, and the condition ranges in severity from self-healing cutaneous lesions to fatal visceral manifestations. There is no vaccine available against visceral leishmaniasis (VL) (also known as kala-azar in India), and current antileishmanial drugs face major drawbacks, including drug resistance, variable efficacy, toxicity and parenteral administration. We report here that n-hexane fractions of Artemisia annua leaves (AAL) and seeds (AAS) possess significant antileishmanial activity against Leishmania donovani promastigotes, with GI 50 of 14.4 and 14.6 mg ml "1 , respectively, and the IC 50 against intracellular amastigotes was found to be 6.6 and 5.05 mg ml "1 , respectively. Changes in the morphology of promastigotes and growth reversibility analysis following treatment confirmed the leishmanicidal effect of the active fractions, which presented no cytotoxic effect on mammalian cells. The antileishmanial activity was mediated via apoptosis, as evidenced by externalization of phosphatidylserine, in situ labelling of DNA fragments by terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling (TUNEL) and cell-cycle arrest at the sub-G 0 /G 1 phase. High-performance thin-layer chromatography (HPTLC) fingerprinting showed that the content of artemisinin in crude bioactive extracts (~1.4 mg per 100 mg n-hexane fraction) was too low to account for the observed antileishmanial activity. Characterization of the active constituents by GC-MS showed that a-amyrinyl acetate, b-amyrine and derivatives of artemisinin were the major constituents in AAL and cetin, EINECS 211-126-2 and artemisinin derivatives in AAS. Our findings indicate the presence of antileishmanial compounds besides artemisinin in the n-hexane fractions of A. annua leaves and seeds.

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Apoptotic Death in Leishmania donovani Promastigotes in Response to Respiratory Chain Inhibition

Cited by 174 publications

References 51 publications

Dual Action of Antimonial Drugs on Thiol Redox Metabolism in the Human Pathogen Leishmania donovani

Dual Action of Antimonial Drugs on Thiol Redox Metabolism in the Human Pathogen Leishmania donovani

RARγ acts as a tumor suppressor in mouse keratinocytes

Extracts of Artemisia annua leaves and seeds mediate programmed cell death in Leishmania donovani

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