Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cells

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. 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).