Lithium, a classic drug in psychiatry, improves nilotinib-mediated antileukemic effects

Lithium, a classic drug in psychiatry, improves nilotinib-mediated antileukemic effects

Author Silva, Janaina Peixoto da Autor UNIFESP Google Scholar
Calgarotto, Andrana K. Autor UNIFESP Google Scholar
Rocha, Katiucha Karolina Autor UNIFESP Google Scholar
Santos, Caroline Palmeira dos Autor UNIFESP Google Scholar
Smaili, Soraya Soubhi Autor UNIFESP Google Scholar
Pereira, Gustavo Jose da Silva Autor UNIFESP Google Scholar
Pericole, Fernando Vieira Google Scholar
Duarte, Adriana da Silva Santos Google Scholar
Saad, Sara Teresinha Olalla Autor UNIFESP Google Scholar
Bincoletto, Claudia Autor UNIFESP Google Scholar
Abstract Although Tyrosine kinase inhibitors (TKIs) that target Bcr-Abl play a key role in Chronic Myeloid Leukemia (CML) therapy, they do not eradicate CML-initiating cells, which lead to the emergence of drug resistance. Here we used the lithium, a GSK-3 inhibitor, to attempt to potentiate the effects of nilotinib against leukemia cells. For this purpose, a K562 leukemia cell line and bone marrow cells from untreated Chronic Myeloid Leukemia (CML) patients, prior to any exposure to TKIs, were used as a model. Our results demonstrated that the combination of lithium + nilotinib (L + N) induced K562-cell death and cleaved caspase-3 when compared to lithium or nilotinib alone, accompanied by GSK-3 beta phosphorylation and Bcr-Abl oncoprotein levels reduction. Interestingly, these events were related to autophagy induction, expressed by increased LC3II protein levels in the group treated with L + N. Furthermore, the clonogenic capacity of progenitor cells from CML patients was drastically reduced by L + N, as well as lithium and nilotinib when used separately. The number of cell aggregates (clusters), were increased by all treatments (L + N, lithium, and nilotinib). This pioneering research has demonstrated that lithium might be of therapeutic value when targeting Bcr-Abl cells with nilotinib because it triggers cell death in addition to exerting classical antiproliferative effects, opening new perspectives for novel target and therapeutic approaches to eradicate CML.
Keywords Nilotinib
Lithium
Cell death
Autophagy
Bcr-Abl
GSK-3 beta
Clonogenicity
Leukemia cells
xmlui.dri2xhtml.METS-1.0.item-coverage Issy-Les-Moulineaux
Language English
Sponsor Fundacao do Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
Novartis
Grant number FAPESP: 12/51215-4
Date 2018
Published in Biomedicine & Pharmacotherapy. Issy-Les-Moulineaux, v. 99, p. 237-244, 2018.
ISSN 0753-3322 (Sherpa/Romeo, impact factor)
Publisher Elsevier France-Editions Scientifiques Medicales Elsevier
Extent 237-244
Origin http://dx.doi.org/10.1016/j.biopha.2018.01.027
Access rights Closed access
Type Article
Web of Science ID WOS:000427436800031
URI https://repositorio.unifesp.br/handle/11600/55908

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