Interaction of Miltefosine with the Lipid and Protein Components of the Erythrocyte Membrane

Moreira, Rodrigo Alves; Mendanha, Sebastião Antônio; Hansen, Daiane; Alonso, Antônio

doi:10.1002/jps.23496

Cited by 25 publications

(22 citation statements)

References 48 publications

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“…Thus, a lipid probe can also reflect the dynamics of the protein component. The fact that MT essentially does not alter the lipid dynamics of phospholipid bilayers at concentrations up to a 25 to 35% molar ratio, as shown in previous work (10,11), suggests that these changes in Leishmania membranes caused by MT are due to its action on membrane proteins.…”

Section: Discussionsupporting

confidence: 61%

“…As described previously, the lipid spin labels were incorporated into the Leishmania membranes first by making films of the spin labels on the bottoms of test tubes (10,11). A 1-l aliquot of a stock solution of the spin label 5-DSA in ethanol (4 mg/ml) was transferred to a glass tube, and after solvent evaporation, 50 l of a Leishmania suspension containing 10 8 cells in phosphate-buffered saline (PBS) was added to the spin-label film, followed by gentle agitation.…”

Section: Chemicalsmentioning

confidence: 99%

“…A 1-l aliquot of a stock solution of the spin label 5-DSA in ethanol (4 mg/ml) was transferred to a glass tube, and after solvent evaporation, 50 l of a Leishmania suspension containing 10 8 cells in phosphate-buffered saline (PBS) was added to the spin-label film, followed by gentle agitation. Following spin labeling, a similar procedure was applied to treat the Leishmania promastigotes with MT (11). An aliquot (1 to 5 l) of a stock solution of MT in ethanol (30 or 100 mg/ml) was used to generate a film in a glass tube at concentrations varying from 30 to 300 g. Spin labeling of Leishmania membrane proteins was performed through incubation for 2 h at 26°C after the addition of an excess of the thiolspecific spin label 6-MSL.…”

Section: Chemicalsmentioning

confidence: 99%

“…To incorporate the MT into the Leishmania membranes, MT films were generated on the bottoms of test tubes, as previously described (10,11). Following the treatment of L. amazonensis promastigotes with MT, cell viability and growth inhibition were assessed via microscopic counting of living and dead cells using the trypan blue exclusion method.…”

Section: Chemicalsmentioning

confidence: 99%

“…Additionally, it was shown that MT causes remarkable increases in the lipid fluidity of stratum corneum membranes when measured directly in tissue but results in only a small alteration of lipid fluidity in a stratum corneum membrane model (10). MT also causes dramatic increases of membrane fluidity in erythrocyte ghost membranes and detergent-resistant membranes (DRMs) (11). In the present study, we further demonstrated that MT exerts a strong effect on the plasma membrane of Leishmania amazonensis promastigotes within the same MT concentration range that inhibits cell growth and causes lysis of the parasite.…”

mentioning

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: Discussionsupporting

confidence: 61%

Section: Chemicalsmentioning

confidence: 99%

Section: Chemicalsmentioning

confidence: 99%

Section: Chemicalsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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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Serum‐derived carcinoembryonic antigen (CEA) activates fibroblasts to induce a local re‐modeling of the extracellular matrix that favors the engraftment of CEA‐expressing tumor cells

Abdul-Wahid

Cydzik

Fischer

et al. 2018

Intl Journal of Cancer

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Elevated levels of the carcinoembryonic antigen (CEA; CEACAM5) in the serum of colorectal cancer (CRC) patients represent a clinical biomarker that correlates with disease recurrence. However, a mechanistic role for soluble CEA (sCEA) in tumor progression and metastasis remains to be established. In this study, we report that sCEA acts as a paracrine factor, activating human fibroblasts by signalling through both the STAT3 and AKT1-mTORC1 pathways, promoting their transition to a cancer-associated fibroblast (CaF) phenotype. sCEA-activated fibroblasts express and secrete high levels of fibronectin, including cellular EDA+-fibronectin (Fn-EDA) that selectively promote the implantation and adherence of CEA-expressing cancer cells. Immunohistochemical analyses of liver tissues derived from CRC patients with elevated levels of sCEA reveal that the expression of cellular Fn-EDA co-registers with CEA-expressing liver metastases. Taken together, these findings indicate a direct role for sCEA as a human fibroblast activation factor, in priming target tissues for the engraftment of CEA-expressing cancer cells, through the differentiation of tissue-resident fibroblasts, resulting in a local change in composition of the extracellular matrix.

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Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

et al. 2017

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This review describes the pharmacokinetic properties of the systemically administered antileishmanial drugs pentavalent antimony, paromomycin, pentamidine, miltefosine and amphotericin B (AMB), including their absorption, distribution, metabolism and excretion and potential drug–drug interactions. This overview provides an understanding of their clinical pharmacokinetics, which could assist in rationalising and optimising treatment regimens, especially in combining multiple antileishmanial drugs in an attempt to increase efficacy and shorten treatment duration. Pentavalent antimony pharmacokinetics are characterised by rapid renal excretion of unchanged drug and a long terminal half-life, potentially due to intracellular conversion to trivalent antimony. Pentamidine is the only antileishmanial drug metabolised by cytochrome P450 enzymes. Paromomycin is excreted by the kidneys unchanged and is eliminated fastest of all antileishmanial drugs. Miltefosine pharmacokinetics are characterized by a long terminal half-life and extensive accumulation during treatment. AMB pharmacokinetics differ per drug formulation, with a fast renal and faecal excretion of AMB deoxylate but a much slower clearance of liposomal AMB resulting in an approximately ten-fold higher exposure. AMB and pentamidine pharmacokinetics have never been evaluated in leishmaniasis patients. Studies linking exposure to effect would be required to define target exposure levels in dose optimisation but have only been performed for miltefosine. Limited research has been conducted on exposure at the drug’s site of action, such as skin exposure in cutaneous leishmaniasis patients after systemic administration. Pharmacokinetic data on special patient populations such as HIV co-infected patients are mostly lacking. More research in these areas will help improve clinical outcomes by informed dosing and combination of drugs.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0570-0) contains supplementary material, which is available to authorized users.

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Interaction of Miltefosine with the Lipid and Protein Components of the Erythrocyte Membrane

Cited by 25 publications

References 48 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

Serum‐derived carcinoembryonic antigen (CEA) activates fibroblasts to induce a local re‐modeling of the extracellular matrix that favors the engraftment of CEA‐expressing tumor cells

Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

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