Dual lysosomal-mitochondrial targeting by antihistamines to eradicate leukaemic cells.

ABSTRACT:

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 as

SUBMITTER: Cornet-Masana JM 

PROVIDER: S-EPMC6796581 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature