Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells

Abstract

Mitochondria have pivotal roles in cellular physiology including energy metabolism, reactive oxygen species production, Ca2+ homeostasis, and apoptosis. Altered mitochondrial morphology and function is a common feature of cancer cells and the regulation of mitochondrial homeostasis has been identified as a key to the response to chemotherapeutic agents in human leukemias. Here, we explore the mechanistic aspects of cytotoxicity produced by thioridazine (TR), an antipsychotic drug that has been investigated for its anticancer potential in human leukemia cellular models. TR exerts selective cytotoxicity against human leukemia cells in vitro. A PCR array provided a general view of the expression of genes involved in cell death pathways. TR immediately produced a pulse of cytosolic Ca2+, followed by mitochondrial uptake, resulting in mitochondrial permeabilization, caspase 9/3 activation, endoplasmic reticulum stress, and apoptosis. Ca2+ chelators, thiol reducer dithiothreitol, or CHOP knockdown prevented TR-induced cell death. TR also exhibited potent cytotoxicity against BCL-2/BCL-xL-overexpressing leukemia cells. Additionally, previous studies have shown that TR exhibits potent antitumor activity in vivo in different solid tumor models. These findings show that TR induces a Ca2+-mediated apoptosis with involvement of mitochondrial permeabilization and ER stress in leukemia and it emphasizes the pharmacological potential of TR as an adjuvant in antitumor chemotherapy.

Repurposing thioridazine for inducing immunogenic cell death in colorectal cancer via eIF2α/ATF4/CHOP and secretory autophagy pathways

“…2 & Supplementary Figure S 4 ). THD has previously been reported to induce ER stress markers in glioblastoma, cervical cancer, and leukemia cells [ 17 , 30 , 33 ]. In this study, we have further elucidated the correlation between THD-induced ER stress, autophagy, and the ICD effect.…”

State-of-the-Art Molecular Oncology in Brazil

“…Cancer therapy now includes conventional chemotherapy, photodynamic therapy, inhibitors of angiogenesis, targeted therapy, immunotherapy, CAR-T cell therapy, oncolytic viruses, and antitumor vaccines [3,4]. Additionally, combined therapies, the development of second-and thirdgeneration drugs, nanotechnological approaches, and drug repurposing have arisen as possible strategies to improve drug responsiveness and overcome drug resistance [5][6][7][8][9]. At last, the possibility of genome edition/correction by the CRISPR-Cas9 methodology represents a promising tool to be employed in treating cancer in the near future [10].…”