Abstract
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.
Highlights
Acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that affects both children and adults [1]
Previous studies suggested that the inhibition of the mitochondrial DNA polymerase, impairment of ATP production, and PI3K/AKT/mTOR signaling pathway are among the mechanisms contributing to TR-induced cell death [8,9,10]
Several drugs employed in cancer therapy induce a protective autophagy response, which can contribute to therapeutic resistance [18], pointing to the pharmacologic inhibition of autophagy as a promising approach to promote/increase tumor cell death elicited by other drugs [19]
Summary
Acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells that affects both children and adults [1]. The combination of lower TR concentrations with other anticancer drugs in a combined chemotherapy might reduce the incidence of undesirable side effects and improve the possible anticancer effect In this regard, the modulation of autophagy has been proposed as a promising therapeutic strategy in cancer therapeutics [14,15]. Several drugs employed in cancer therapy induce a protective autophagy response, which can contribute to therapeutic resistance [18], pointing to the pharmacologic inhibition of autophagy as a promising approach to promote/increase tumor cell death elicited by other drugs [19]. Our data showed that TR induces a potent and selective cell death in T-ALL cells in vitro and that autophagy inhibition potentiates its cytotoxicity, constituting a promising strategy for ALL chemotherapy
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