Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells

Acute myeloid leukemia (AML) is an hematologic neoplasia characterized by the accumulation of transformed immature myeloid cells in bone marrow. Although the response rate to induction therapy is high, survival rate 5-year after diagnosis is still low, highlighting the necessity of new novel agents....

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Main Authors:	Cornet-Masana, Josep Maria, Moreno-Martínez, Daniel, Lara-Castillo, María Carmen, Nomdedeu, Meritxell, Etxabe, Amaia, Tesi, Niccolò, Pratcorona, Marta, Esteve, Jordi, Risueño, Ruth M.
Format:	Online
Language:	English
Published:	Impact Journals LLC 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029623/

id	pubmed-5029623
recordtype	oai_dc
spelling	pubmed-50296232016-09-29 Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells Cornet-Masana, Josep Maria Moreno-Martínez, Daniel Lara-Castillo, María Carmen Nomdedeu, Meritxell Etxabe, Amaia Tesi, Niccolò Pratcorona, Marta Esteve, Jordi Risueño, Ruth M. Research Paper Acute myeloid leukemia (AML) is an hematologic neoplasia characterized by the accumulation of transformed immature myeloid cells in bone marrow. Although the response rate to induction therapy is high, survival rate 5-year after diagnosis is still low, highlighting the necessity of new novel agents. To identify agents with the capability to abolish the self-renewal capacity of AML blasts, an in silico screening was performed to search for small molecules that induce terminal differentiation. Emetine, a hit compound, was validated for its anti-leukemic effect in vitro, ex vivo and in vivo. Emetine, a second-line anti-protozoa drug, differentially reduced cell viability and clonogenic capacity of AML primary patient samples, sparing healthy blood cells. Emetine treatment markedly reduced AML burden in bone marrow of xenotransplanted mice and decreased self-renewal capacity of the remaining engrafted AML cells. Emetine also synergized with commonly used chemotherapeutic agents such as ara-C. At a molecular level, emetine treatment was followed by a reduction in HIF-1α protein levels. This study validated the anti-leukemiceffect of emetine in AML cell lines, a group of diverse AML primary samples, and in a human AML-transplanted murine model, sparing healthy blood cells. The selective anti-leukemic effect of emetine together with the safety of the dose range required to exert this effect support the development of this agent in clinical practice. Impact Journals LLC 2016-03-15 /pmc/articles/PMC5029623/ /pubmed/26992240 http://dx.doi.org/10.18632/oncotarget.8096 Text en Copyright: © 2016 Cornet-Masana et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Cornet-Masana, Josep Maria Moreno-Martínez, Daniel Lara-Castillo, María Carmen Nomdedeu, Meritxell Etxabe, Amaia Tesi, Niccolò Pratcorona, Marta Esteve, Jordi Risueño, Ruth M.
spellingShingle	Cornet-Masana, Josep Maria Moreno-Martínez, Daniel Lara-Castillo, María Carmen Nomdedeu, Meritxell Etxabe, Amaia Tesi, Niccolò Pratcorona, Marta Esteve, Jordi Risueño, Ruth M. Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells
author_facet	Cornet-Masana, Josep Maria Moreno-Martínez, Daniel Lara-Castillo, María Carmen Nomdedeu, Meritxell Etxabe, Amaia Tesi, Niccolò Pratcorona, Marta Esteve, Jordi Risueño, Ruth M.
author_sort	Cornet-Masana, Josep Maria
title	Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells
title_short	Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells
title_full	Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells
title_fullStr	Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells
title_full_unstemmed	Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells
title_sort	emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells
description	Acute myeloid leukemia (AML) is an hematologic neoplasia characterized by the accumulation of transformed immature myeloid cells in bone marrow. Although the response rate to induction therapy is high, survival rate 5-year after diagnosis is still low, highlighting the necessity of new novel agents. To identify agents with the capability to abolish the self-renewal capacity of AML blasts, an in silico screening was performed to search for small molecules that induce terminal differentiation. Emetine, a hit compound, was validated for its anti-leukemic effect in vitro, ex vivo and in vivo. Emetine, a second-line anti-protozoa drug, differentially reduced cell viability and clonogenic capacity of AML primary patient samples, sparing healthy blood cells. Emetine treatment markedly reduced AML burden in bone marrow of xenotransplanted mice and decreased self-renewal capacity of the remaining engrafted AML cells. Emetine also synergized with commonly used chemotherapeutic agents such as ara-C. At a molecular level, emetine treatment was followed by a reduction in HIF-1α protein levels. This study validated the anti-leukemiceffect of emetine in AML cell lines, a group of diverse AML primary samples, and in a human AML-transplanted murine model, sparing healthy blood cells. The selective anti-leukemic effect of emetine together with the safety of the dose range required to exert this effect support the development of this agent in clinical practice.
publisher	Impact Journals LLC
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029623/
_version_	1613655928105598976

Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells

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