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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.<\/jats:p>","DOI":"10.3390\/life12101477","type":"journal-article","created":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T04:07:07Z","timestamp":1663906027000},"page":"1477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells"],"prefix":"10.3390","volume":"12","author":[{"given":"Vivian W. R.","family":"Moraes","sequence":"first","affiliation":[{"name":"Center for Natural and Human Sciences, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"},{"name":"Department of Molecular Medicine, Scripps Research Institute, La Jolla, San Diego, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian M.","family":"Santos","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0521-1056","authenticated-orcid":false,"given":"Eloah R.","family":"Suarez","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7915-0081","authenticated-orcid":false,"given":"Let\u00edcia S.","family":"Ferraz","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3700-3670","authenticated-orcid":false,"given":"Rayssa de Mello","family":"Lopes","sequence":"additional","affiliation":[{"name":"Center for Natural and Human Sciences, Federal University of ABC, Santo Andr\u00e9 09210-580, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuliana P.","family":"Mognol","sequence":"additional","affiliation":[{"name":"Bluestar Genomics, San Diego, CA 92121, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2401-1113","authenticated-orcid":false,"given":"Joana D.","family":"Campeiro","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04044-020, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2937-8109","authenticated-orcid":false,"given":"Jo\u00e3o A.","family":"Machado-Neto","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-000, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio D.","family":"Nascimento","sequence":"additional","affiliation":[{"name":"Interdisciplinary Center of Biochemistry Investigation, University of Mogi das Cruzes, Mogi das Cruzes 08780-911, SP, Brazil"},{"name":"Department of Molecular Biology, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04021-001, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6437-4923","authenticated-orcid":false,"given":"Mirian A. 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