Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cellsResearch in context
Background: Despite great efforts to identify druggable molecular targets for AML, there remains an unmet need for more effective therapies. Methods: An in silico screening was performed using Connectivity Maps to identify FDA-approved drugs that may revert an early leukaemic transformation gene sig...
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doaj-b2c84a711dbd456585fea65b0bb48e742020-11-25T01:35:53ZengElsevierEBioMedicine2352-39642019-09-0147221234Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cellsResearch in contextJosep M. Cornet-Masana0Antònia Banús-Mulet1José M. Carbó2Miguel Ángel Torrente3Francesca Guijarro4Laia Cuesta-Casanovas5Jordi Esteve6Ruth M. Risueño7Josep Carreras Leukaemia Research Institute (IJC). Barcelona, Spain; Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP). Badalona, Spain; Faculty of Medicine, University of Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC). Barcelona, Spain; Faculty of Pharmacy, University of Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC). Barcelona, SpainFaculty of Medicine, University of Barcelona, Spain; Department of Haematology, Hospital Clínic, Barcelona, SpainFaculty of Medicine, University of Barcelona, Spain; Department of Haematology, Hospital Clínic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC). Barcelona, Spain; Faculty of Biosciences, Autonomous University of Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC). Barcelona, Spain; Faculty of Medicine, University of Barcelona, Spain; Department of Haematology, Hospital Clínic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, SpainJosep Carreras Leukaemia Research Institute (IJC). Barcelona, Spain; Corresponding author at: Josep Carreras Leukaemia Research Institute, Campus ICO-GTP, Crta Can Ruti. Camí de les Escoles, s/n, 08916 Badalona Barcelona, Spain.Background: Despite great efforts to identify druggable molecular targets for AML, there remains an unmet need for more effective therapies. Methods: An in silico screening was performed using Connectivity Maps to identify FDA-approved drugs that may revert an early leukaemic transformation gene signature. Hit compounds were validated in AML cell lines. Cytotoxic effects were assessed both in primary AML patient samples and healthy donor blood cells. Xenotransplantation assays were undertaken to determine the effect on engraftment of hit compounds. The mechanism of action responsible for the antileukaemic effect was studied focussing on lysosomes and mitochondria. Findings: We identified a group of antihistamines (termed ANHAs) with distinct physicochemical properties associated with their cationic-amphiphilic nature, that selectively killed leukaemic cells. ANHAs behaved as antileukaemic agents against primary AML samples ex vivo, sparing healthy cells. Moreover, ANHAs severely impaired the in vivo leukaemia regeneration capacity. ANHAs' cytotoxicity relied on simultaneous mitochondrial and lysosomal disruption and induction of autophagy and apoptosis. The pharmacological effect was exerted based on their physicochemical properties that permitted the passive targeting of both organelles, without the involvement of active molecular recognition. Interpretation: Dual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for leukaemia treatment, supporting the further clinical development. Fund: This work was funded by the Fundación Mutua Madrileña (RMR), CaixaImpulse (RMR), the Spanish Ministry of Economy (RMR), the Josep Carreras International Leukaemia Foundation (RMR), l'Obra Social “La Caixa” (RMR), and Generalitat de Catalunya (IJC). Keywords: Leukaemia, Antihistamines, Ebastine, Lysosomes, Mitochondriahttp://www.sciencedirect.com/science/article/pii/S2352396419305432 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Josep M. Cornet-Masana Antònia Banús-Mulet José M. Carbó Miguel Ángel Torrente Francesca Guijarro Laia Cuesta-Casanovas Jordi Esteve Ruth M. Risueño |
spellingShingle |
Josep M. Cornet-Masana Antònia Banús-Mulet José M. Carbó Miguel Ángel Torrente Francesca Guijarro Laia Cuesta-Casanovas Jordi Esteve Ruth M. Risueño Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cellsResearch in context EBioMedicine |
author_facet |
Josep M. Cornet-Masana Antònia Banús-Mulet José M. Carbó Miguel Ángel Torrente Francesca Guijarro Laia Cuesta-Casanovas Jordi Esteve Ruth M. Risueño |
author_sort |
Josep M. Cornet-Masana |
title |
Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cellsResearch in context |
title_short |
Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cellsResearch in context |
title_full |
Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cellsResearch in context |
title_fullStr |
Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cellsResearch in context |
title_full_unstemmed |
Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cellsResearch in context |
title_sort |
dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cellsresearch in context |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2019-09-01 |
description |
Background: Despite great efforts to identify druggable molecular targets for AML, there remains an unmet need for more effective therapies. Methods: An in silico screening was performed using Connectivity Maps to identify FDA-approved drugs that may revert an early leukaemic transformation gene signature. Hit compounds were validated in AML cell lines. Cytotoxic effects were assessed both in primary AML patient samples and healthy donor blood cells. Xenotransplantation assays were undertaken to determine the effect on engraftment of hit compounds. The mechanism of action responsible for the antileukaemic effect was studied focussing on lysosomes and mitochondria. Findings: We identified a group of antihistamines (termed ANHAs) with distinct physicochemical properties associated with their cationic-amphiphilic nature, that selectively killed leukaemic cells. ANHAs behaved as antileukaemic agents against primary AML samples ex vivo, sparing healthy cells. Moreover, ANHAs severely impaired the in vivo leukaemia regeneration capacity. ANHAs' cytotoxicity relied on simultaneous mitochondrial and lysosomal disruption and induction of autophagy and apoptosis. The pharmacological effect was exerted based on their physicochemical properties that permitted the passive targeting of both organelles, without the involvement of active molecular recognition. Interpretation: Dual targeting of lysosomes and mitochondria constitutes a new promising therapeutic approach for leukaemia treatment, supporting the further clinical development. Fund: This work was funded by the Fundación Mutua Madrileña (RMR), CaixaImpulse (RMR), the Spanish Ministry of Economy (RMR), the Josep Carreras International Leukaemia Foundation (RMR), l'Obra Social “La Caixa” (RMR), and Generalitat de Catalunya (IJC). Keywords: Leukaemia, Antihistamines, Ebastine, Lysosomes, Mitochondria |
url |
http://www.sciencedirect.com/science/article/pii/S2352396419305432 |
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