Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Autor(es)

Colturato-Kido, Carina ; Lopes, Rayssa M. ; Medeiros, Hyllana C. D. ; Costa, Claudia A. ; Prado-Souza, Laura E. L. ; Ferraz, Leticia S. ; Rodrigues, Tiago

• Tipo de documento: Artigo Científico
• Fonte: LIFE-BASEL; v. 11, n. 4, p. 14-pg., 2021-04-01.

Resumo

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a "double-edged sword" contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL. (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
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/25747-5 - Alterações de morfologia e dinâmica mitocondriais no câncer: compreensão da biologia tumoral e prospecção de novos alvos terapêuticos
• Beneficiário: Tiago Rodrigues
• Modalidade de apoio: Auxílio à Pesquisa - Regular