Lithium, a classic drug in psychiatry, improves nilotinib-mediated antileukemic effects
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2018
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Silva, Janaina Peixoto da [UNIFESP]
Calgarotto, Andrana K. [UNIFESP]
Rocha, Katiucha Karolina [UNIFESP]
Santos, Caroline Palmeira dos [UNIFESP]
Smaili, Soraya Soubhi [UNIFESP]
Pereira, Gustavo Jose da Silva [UNIFESP]
Pericole, Fernando Vieira
Duarte, Adriana da Silva Santos
Saad, Sara Teresinha Olalla [UNIFESP]
Bincoletto, Claudia [UNIFESP]
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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.
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Biomedicine & Pharmacotherapy. Issy-Les-Moulineaux, v. 99, p. 237-244, 2018.