Abstract
BackgroundTreatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates. Leukemia stem cells (LSC) are responsible for the initiation and maintenance of AML due to their stem-cell properties. Differentiation therapies aim to abrogate the self-renewal capacity and diminish blast lifespan.MethodsAn in silico screening was designed to search for FDA-approved small molecules that potentially induce differentiation of AML cells. Bromocriptine was identified and validated in an in vitro screening. Bromocriptine is an approved drug originally indicated for Parkinson’s disease, acromegaly, hyperprolactinemia and galactorrhoea, and recently repositioned for diabetes mellitus.ResultsTreatment with bromocriptine reduced cell viability of AML cells by activation of the apoptosis program and induction of myeloid differentiation. Moreover, the LSC-enriched primitive AML cell fraction was more sensitive to the presence of bromocriptine. In fact, bromocriptine decreased the clonogenic capacity of AML cells. Interestingly, a negligible effect is observed in healthy blood cells and hematopoietic stem/progenitor cells.ConclusionsOur results support the use of bromocriptine as an anti-AML drug in a repositioning setting and the further clinical validation of this preclinical study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1007-5) contains supplementary material, which is available to authorized users.
Highlights
Treatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates
In silico screening Gene signature associated with Phorbol myristate acetate (PMA)-induced differentiation in HL60 cells was obtained from GSE982 and analysed as described previously [10, 11]
As targeted therapies aiming to force AML blast cells to terminally differentiate will result in cell death, a PMA-induced differentiation-associated gene expression profile was identified and interrogated against the Connectivity Map database [12]
Summary
Treatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates. Current available chemotherapy may have reached its limits In this context, drug repositioning appears as a promising strategy for AML as safety and pharmacokinetic profiles of candidates are Leukemia stem cells (LSC) have been described in the majority of AML patients and constitute a cell fraction with self-renewal and differentiation properties [3]. Drug repositioning appears as a promising strategy for AML as safety and pharmacokinetic profiles of candidates are Leukemia stem cells (LSC) have been described in the majority of AML patients and constitute a cell fraction with self-renewal and differentiation properties [3] Due to their stem-cell like properties, relapse episodes and refractoriness to treatment were associated to LSC function [4]. Differentiation therapies hold promise as a therapeutic approach to target LSCs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
