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

• Published in: Life (Basel, Switzerland) Vol. 11; no. 4; p. 365
• Main Authors: Colturato-Kido, Carina, Lopes, Rayssa M, Medeiros, Hyllana C D, Costa, Claudia A, Prado-Souza, Laura F L, Ferraz, Letícia S, Rodrigues, Tiago
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20-04-2021; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; Acute lymphoblastic leukemia; AKT protein; Anticancer properties; Antihistamines; Antipsychotics; Antitumor activity; Apoptosis; Autophagy; Blood cells; Cancer therapies; Caspase-8; Cell activation; Cell death; Cell survival; Chemotherapy; Chronic myeloid leukemia; Cytotoxicity; Data analysis; Drug development; Drug resistance; Drugs; Kinases; Laboratories; Leukemia; Lymphatic leukemia; MAP kinase; Mcl-1 protein; Membranes; Metabolic pathways; Mitochondrial DNA; Mortality; Myeloid leukemia; Phagocytosis; Phenothiazine; Phenothiazines; Promethazine; Proteins; Psychotropic drugs; Software; Stem cells; Thioridazine; Toxicity; viability; St Louis Missouri; United States > US; apoptosis; autophagy; acute lymphoblastic leukemia; thioridazine; viability
• ISSN: 2075-1729; 2075-1729
• DOI: 10.3390/life11040365

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.