Josep 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, Spain.
Josep Carreras Leukaemia Research Institute (IJC). Barcelona, Spain; Faculty of Pharmacy, University of Barcelona, Spain.
EBioMedicine. 2019 Sep;47:221-234. doi: 10.1016/j.ebiom.2019.08.021. Epub 2019 Aug 28.
Despite great efforts to identify druggable molecular targets for AML, there remains an unmet need for more effective therapies.
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.
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.
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).
尽管在寻找 AML 的可成药分子靶标方面付出了巨大努力，但仍需要更有效的治疗方法。
使用 Connectivity Maps 进行计算机筛选，以鉴定可能逆转早期白血病转化基因特征的已批准用于治疗的药物。在 AML 细胞系中验证命中化合物。在原发性 AML 患者样本和健康供体血细胞中评估细胞毒性作用。进行异种移植实验以确定命中化合物对植入的影响。研究负责抗白血病作用的作用机制，重点关注溶酶体和线粒体。
我们发现了一组具有独特物理化学特性的抗组胺药（称为 ANHAs），与它们的阳离子两亲性质有关，可选择性杀死白血病细胞。ANHAs 作为抗白血病剂在体外对原发性 AML 样本起作用，而对健康细胞无影响。此外，ANHAs 严重损害了体内白血病再生能力。ANHAs 的细胞毒性依赖于线粒体和溶酶体的同时破坏以及自噬和凋亡的诱导。药理作用是基于其物理化学性质发挥的，这些性质允许被动靶向这两种细胞器，而无需主动的分子识别参与。
溶酶体和线粒体的双重靶向为白血病治疗提供了一种新的有前途的治疗方法，支持进一步的临床开发。资金来源：这项工作得到了 Fundación Mutua Madrileña（RMR）、CaixaImpulse（RMR）、西班牙经济部（RMR）、Josep Carreras 国际白血病基金会（RMR）、l'Obra Social "La Caixa"（RMR）和加泰罗尼亚政府（IJC）的资助。
