Cellular targets of mefloquine

Ghosh, Debasish Kumar; Kumar, Abhishek; Ranjan, Akash

doi:10.1016/j.tox.2021.152995

Cited by 10 publications

(13 citation statements)

References 77 publications

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“…With the purpose of permeabilising MC granules, we have selected mefloquine, an approved drug for prophylaxis and treatment of malaria. Mefloquine is a quinoline‐based compound that interferes with lipid binding proteins, prevents heme polymerisation and inhibits protein synthesis by targeting cytosolic 80S ribosome of Plasmodium malariae 13 . Furthermore, previous studies suggest that the drug exerts anti‐malarial activity by penetrating into acidic endosomal compartments of the parasite 14 .…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, previous studies suggest that the drug exerts anti‐malarial activity by penetrating into acidic endosomal compartments of the parasite 14 . In human cells it is known that mefloquine can diffuse over membranes after interaction with negatively charged phospholipids and also to interact with several types of receptors involved in the membrane transport of various small molecules 13 …”

Section: Introductionmentioning

confidence: 99%

“…14 In human cells it is known that mefloquine can diffuse over membranes after interaction with negatively charged phospholipids and also to interact with several types of receptors involved in the membrane transport of various small molecules. 13 Since MC secretory granules are acidic, endolysosomal-like organelles, we have reasoned that mefloquine may also have cytotoxic effects on MCs via a mechanism analogous to that on Plasmodium malariae. Our idea is supported by previous reports showing that mouse MCs are highly sensitive to mefloquine.…”

Section: Introductionmentioning

confidence: 99%

“…Mefloquine is a quinoline‐based compound that interferes with lipid binding proteins, prevents heme polymerisation and inhibits protein synthesis by targeting cytosolic 80S ribosome of Plasmodium malariae . 13 Furthermore, previous studies suggest that the drug exerts anti‐malarial activity by penetrating into acidic endosomal compartments of the parasite. 14 In human cells it is known that mefloquine can diffuse over membranes after interaction with negatively charged phospholipids and also to interact with several types of receptors involved in the membrane transport of various small molecules.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mefloquine causes selective mast cell apoptosis in cutaneous mastocytosis lesions by a secretory granule‐mediated pathway

Lampinen

Hagforsen

Weström

et al. 2022

Experimental Dermatology

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Mastocytosis is a KIT‐related myeloproliferative disease characterised by abnormal expansion of neoplastic mast cells (MC) in the skin or virtually any other organ system. The cutaneous form of adult‐onset mastocytosis is almost invariably combined with indolent systemic involvement for which curative therapy is yet not available. Here we evaluated a concept of depleting cutaneous MCs in mastocytosis lesions ex vivo by targeting their secretory granules. Skin biopsies from mastocytosis patients were incubated with or without mefloquine, an antimalarial drug known to penetrate into acidic organelles such as MC secretory granules. Mefloquine reduced the number of dermal MCs without affecting keratinocyte proliferation or epidermal gross morphology at drug concentrations up to 40 μM. Flow cytometric analysis of purified dermal MCs showed that mefloquine‐induced cell death was mainly due to apoptosis and accompanied by caspase‐3 activation. However, caspase inhibition provided only partial protection against mefloquine‐induced cell death, indicating predominantly caspase‐independent apoptosis. Further assessments revealed that mefloquine caused an elevation of granule pH and a corresponding decrease in cytosolic pH, suggesting drug‐induced granule permeabilisation. Extensive damage to the MC secretory granules was confirmed by transmission electron microscopy analysis. Further, blockade of granule acidification or serine protease activity prior to mefloquine treatment protected MCs from apoptosis, indicating that granule acidity and granule‐localised serine proteases play major roles in the execution of mefloquine‐induced cell death. Altogether, these findings reveal that mefloquine induces selective apoptosis of MCs by targeting their secretory granules and suggest that the drug may potentially extend its range of medical applications.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%