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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

nhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cell

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Colturato-Kido, Carina [1] ; Lopes, Rayssa M. [1] ; Medeiros, Hyllana C. D. [1] ; Costa, Claudia A. [2] ; Prado-Souza, Laura E. L. [1] ; Ferraz, Leticia S. [1] ; Rodrigues, Tiago [1]
Total Authors: 7
[1] Univ Fed ABC UFABC, Ctr Ciencias Nat & Humanas CCNH, BR-09210580 Santo Andre, SP - Brazil
[2] Univ Mogi das Cruzes UMC, Ctr Interdisciplinar Invest Bioquim CIIB, BR-08780911 Mogi Das Cruzes, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: LIFE-BASEL; v. 11, n. 4 APR 2021.
Web of Science Citations: 0

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)

FAPESP's process: 16/07367-5 - Investigation of Phenothiazine-Induced Cell Death Mechanisms In Tumor Cells: Changes in Gene Expression, Role of Bcl-2 Family Proteins, and ER Stress
Grantee:Tiago Rodrigues
Support type: Regular Research Grants
FAPESP's process: 18/25747-5 - Alterations of mitochondrial morphology and dynamics in cancer: understanding of tumor biology and prospecting new therapeutic targets
Grantee:Tiago Rodrigues
Support type: Regular Research Grants