Miltefosine induces apoptosis in arsenite-resistant Leishmania donovani promastigotes through mitochondrial dysfunction

Verma, Navin Kumar; Singh, Gaganmeet; Dey, Chinmoy Sankar

doi:10.1016/j.exppara.2006.10.007

Cited by 91 publications

(82 citation statements)

References 45 publications

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“…A comparison of our results regarding cell counts ( Fig. 5 and 6) with the data reported by Verma et al (30) is relevant in this context. These authors treated L. donovani promastigotes (5 ϫ 10 6 cells/ml) with 25 M MT (IC 50 ), and no effect of the drug was observed until at least 4 h after treatment.…”

Section: Discussionmentioning

confidence: 61%

“…5). The explanation for the higher drug/cell ratio may be associated with the low number of cells/ml used by Verma et al (30); this number is commonly used but seems to be less similar to that encountered under physiological conditions. In human blood, MT must undergo partitioning over the membranes of all cells present in the blood and albumin, where there are approximately 5 ϫ 10 9 erythrocytes/ml.…”

Section: Discussionmentioning

confidence: 96%

“…It has been demonstrated that, at its IC 50 , MT is able to induce programmed apoptosis-like cell death in Leishmania donovani (29,30) and L. amazonensis (31) promastigotes. A comparison of our results regarding cell counts ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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Miltefosine Increases Lipid and Protein Dynamics in Leishmania amazonensis Membranes at Concentrations Similar to Those Needed for Cytotoxicity Activity

Moreira

Mendanha

Fernandes

et al. 2014

Antimicrob Agents Chemother

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b Miltefosine (MT) is a membrane-active alkylphospholipid licensed for the topical treatment of breast cancer skin metastases and the oral treatment of leishmaniasis, although its mechanism of action remains unclear. Electron paramagnetic resonance (EPR) spectroscopy of a spin-labeled lipid and a thiol-specific spin label in the plasma membrane of Leishmania promastigotes showed that MT causes dramatic increases in membrane dynamics. Although these alterations can be detected using a spin-labeled lipid, our experimental results indicated that MT interacts predominantly with the protein component of the membrane. Cell lysis was also detected by analyzing the supernatants of centrifuged samples for the presence of spin-labeled membrane fragments and cytoplasmic proteins. Using a method for the rapid incorporation of MT into the membrane, these effects were measured immediately after treatment under the same range of MT concentrations that cause cell growth inhibition. Cytotoxicity, estimated via microscopic counting of living and dead cells, indicated ϳ70% cell death at the concentration of MT at which EPR spectroscopy detected a significant change in membrane dynamics. After this initial impact on the number of viable parasites, the processes of cell death and growth continued during the first 4 h of incubation. The EPR spectra of spin-labeled membrane-bound proteins were consistent with more expanded and solvent-exposed protein conformations, suggesting a detergent-like action. Thus, MT may form micelle-like structures around polypeptide chains, and proteins with a higher hydrophobicity may induce the penetration of hydrophilic groups of MT into the membrane, causing its rupture. L eishmaniasis is caused by protozoan parasites of over 20 Leishmania species and is transmitted to humans via the bite of infected female sand flies. There are three main types of leishmaniasis: cutaneous (the most common form), visceral (the most severe clinical manifestation, which is fatal if untreated), and mucocutaneous. According to a recent report from the World Health Organization (WHO) (1), there are an estimated 1.3 million new cases of leishmaniasis worldwide and an estimated 20,000 to 30,000 deaths caused by these parasites annually.Miltefosine (MT) was the first oral drug approved for use for the treatment of visceral and cutaneous leishmaniasis and is currently registered for leishmaniasis treatment in India (2002, as Impavido), Germany (2004), and Colombia (2005) (2). This drug is also used clinically for the topical treatment of skin metastases associated with breast cancer and cutaneous lymphoma (3). MT has shown high cure rates in the treatment of visceral (4), cutaneous (5), and mucocutaneous (6) leishmaniasis. Although many studies have been conducted to identify the mechanisms underlying the action of MT against tumor cells (3) and parasites (7), these mechanisms have not yet been determined. However, due to its chemical structure, which provides MT with a high membrane affinity, the primary molecular targets of MT...

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 96%

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Miltefosine Increases Lipid and Protein Dynamics in Leishmania amazonensis Membranes at Concentrations Similar to Those Needed for Cytotoxicity Activity

Moreira

Mendanha

Fernandes

et al. 2014

Antimicrob Agents Chemother

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“…2B) after miltefosine treatment indicated the possibility of necrosis-like death in later stages. This result is not surprising because cells at a very advanced stage of apoptosis resemble necrotic cells, which causes difficulties in the ability to discriminate between late apoptotic and necrotic cells (Verma et al 2007).…”

mentioning

confidence: 96%

“…Moreover, miltefosine has been successfully used to treat patients with antimony-resistant VL, VL in children and CL in South America (Croft & Engel 2006 (Escobar et al 2002, Santa-Rita et al 2004, CabreraSerra et al 2007). In addition, the induction of apoptosis following miltefosine treatment has already been reported in L. donovani (Paris et al 2004, Verma et al 2007). Our study aimed to evaluate its mode of action against L. amazonensis to delineate the implications of miltefosine treatment in this parasite.…”

mentioning

confidence: 98%

Miltefosine induces programmed cell death in Leishmania amazonensis promastigotes

Marinho

Goncalves

Oliveira

et al. 2011

Mem. Inst. Oswaldo Cruz

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In the current study, we evaluated the mechanism of action of miltefosine, which is the first effective and safe oral treatment for visceral leishmaniasis, in Leishmania amazonensis promastigotes. Miltefosine induced a process of programmed cell death, which was determined by the externalization of phosphatidylserine, the incorporation of propidium iodide, cell-cycle arrest at the sub-G0/G1 phase and DNA fragmentation into oligonucleosome-sized fragments. Despite the intrinsic variation that is detected in Leishmania spp, our results indicate that miltefosine causes apoptosis-like death in L. amazonensis promastigote cells using a similar process that is observed in Leishmania donovani

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Leishmanicidal Evaluation of Novel Synthetic Chromenes

Heidary

Foroumadi

Ardestani

et al. 2008

Archiv der Pharmazie

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In the present paper, twelve chromenes were synthesized by coupling of 2,2,8,8-tetramethyl-8H-pyrano[2,3-f]chroman-4-one 1 with various aryl and benzylmagnesium chlorides. The synthetic compounds were examined for in-vitro activity against Leishmania major, and some of them displayed efficient anti-leishmanial activity. Among the compounds tested, compounds 9 (4-(2-chloro-benzylidene)-2,2,8,8-tetramethyl-3,4-dihydro-2H,8H-pyrano[2,3-f]chromene 9a and 4-(2-chloro-benzyl)-2,2,8,8-tetramethyl-2H,8H-pyrano[2,3-f]chromene 9b) were the most active with an inhibitory activity of 73.4%.

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Miltefosine induces apoptosis in arsenite-resistant Leishmania donovani promastigotes through mitochondrial dysfunction

Cited by 91 publications

References 45 publications

Miltefosine Increases Lipid and Protein Dynamics in Leishmania amazonensis Membranes at Concentrations Similar to Those Needed for Cytotoxicity Activity

Miltefosine Increases Lipid and Protein Dynamics in Leishmania amazonensis Membranes at Concentrations Similar to Those Needed for Cytotoxicity Activity

Miltefosine induces programmed cell death in Leishmania amazonensis promastigotes

Leishmanicidal Evaluation of Novel Synthetic Chromenes

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