Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cells
Cornet-Masana, Josep Maria (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Banús, Antònia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Carbó, José María (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Torrente, M. Á. (Hospital Clínic i Provincial de Barcelona)
Guijarro, Francesca (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Cuesta-Casanovas, Laia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Esteve Reyner, Jordi (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Risueño, Ruth M. (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Universitat Autònoma de Barcelona

Data:	2019
Resum:	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).
Ajuts:	Ministerio de Ciencia e Innovación RYC-2011-07998 Ministerio de Economía y Competitividad IEDI-2016-00740 Ministerio de Economía y Competitividad SAF2015-66721-P
Nota:	Altres ajuts: This work was funded by the Fundación Mutua Madrileña (RMR), CaixaImpulse the Josep Carreras International Leukaemia Foundation (RMR), l'Obra Social "La Caixa"-Fundació Bancària "La Caixa" (RMR), and CERCA Programme/Generalitat de Catalunya (IJC). RMR had full access to all the data in the study and had final responsibility for the decision to submit for publication. Funding sources provided economical support to the experimental work presented here.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Antihistamines ; Ebastine ; Leukaemia ; Lysosomes ; Mitochondria
Publicat a:	EBioMedicine, Vol. 47 (september 2019) , p. 221-234, ISSN 2352-3964

DOI: 10.1016/j.ebiom.2019.08.021
PMID: 31473184

14 p, 2.6 MB

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