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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

AMPK activation induced by promethazine increases NOXA expression and Beclin-1 phosphorylation and drives autophagy-associated apoptosis in chronic myeloid leukemia

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Autor(es):
Medeiros, Hyllana C. D. [1] ; Colturato-Kido, Carina [1] ; Ferraz, Leticia S. [1] ; Costa, Claudia A. [2] ; Moraes, Vivian W. R. [3] ; Paredes-Gamero, Edgar Julian [4] ; Tersariol, Ivarne L. S. [5] ; Rodrigues, Tiago [1]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Fed Univ ABC, Ctr Nat & Human Sci, UFABC, CCNH, Ave Estados 5001, Bloco A, Torre 3, Sala 623, BR-09021058 Santo Andre, SP - Brazil
[2] Univ Mogi das Cruzes, Interdisciplinary Ctr Biochem Invest, CIIB, Mogi das Cruzes, SP - Brazil
[3] Scripps Res Inst, Dept Mol Med, La Jolla, CA - USA
[4] Univ Fed Mato Grosso do Sul, Sch Pharmaceut Sci, UFMS, Campo Grande, MS - Brazil
[5] Univ Fed Sao Paulo, Sao Paulo Sch Med, Dept Biochem, Unifesp, Sao Paulo, SP - Brazil
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: Chemico-Biological Interactions; v. 315, JAN 5 2020.
Citações Web of Science: 0
Resumo

Relapse and drug resistance is still major challenges in the treatment of leukemia. Promethazine, an antihistaminic phenothiazine derivative, has been used to prevent chemotherapy-induced emesis, although there is no report about its antitumor potential. Thus, we evaluated the promethazine cytotoxicity against several leukemia cells and the underlying mechanisms were investigated. Promethazine exhibited potent and selective cytotoxicity against all leukemia cell types in vitro at clinically relevant concentrations. Philadelphia positive chronic myeloid leukemia (CML) K562 cells were the most sensitive cell line. The cytotoxicity of promethazine in these cells was triggered by the activation of AMPK and inhibition of PI3K/AKT/mTOR pathway. The subsequent downstream effects were NOXA increase, MCL-1 decrease, and Beclin-1 activation, resulting in autophagy-as-sociated apoptosis. These data highlight targeting autophagy may represent an interesting strategy in CML therapy, and also the antitumor potential of promethazine by acing in AMPK and PI3K/AKT/mTOR signaling pathways. Since this drug is currently used with relative low side effects, its repurposing may represent a new therapeutic opportunity for leukemia treatment. (AU)

Processo FAPESP: 16/07367-5 - Investigação dos Mecanismos de Indução de Morte Celular por Fenotiazinas em Células Tumorais: Modulação da Expressão Gênica e Papel das Proteínas da Família BCL-2 e Estresse do Retículo Endoplasmático
Beneficiário:Tiago Rodrigues
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 12/12247-8 - Novas aplicações de fenotiazinas e paladaciclos: utilização de sistemas nanoestruturados para o estudo dos mecanismos de morte em células tumorais
Beneficiário:Tiago Rodrigues
Linha de fomento: Auxílio à Pesquisa - Regular