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Targeting Ca2+ and Mitochondrial Homeostasis by Antipsychotic Thioridazine in Leukemia Cells.
Moraes, Vivian W R; Santos, Vivian M; Suarez, Eloah R; Ferraz, Letícia S; Lopes, Rayssa de Mello; Mognol, Giuliana P; Campeiro, Joana D; Machado-Neto, João A; Nascimento, Fabio D; Hayashi, Mirian A F; Tersariol, Ivarne L S; Newmeyer, Donald D; Rodrigues, Tiago.
Afiliação
  • Moraes VWR; Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil.
  • Santos VM; Department of Molecular Medicine, Scripps Research Institute, La Jolla, San Diego, CA 92037, USA.
  • Suarez ER; Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil.
  • Ferraz LS; Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil.
  • Lopes RM; Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil.
  • Mognol GP; Center for Natural and Human Sciences, Federal University of ABC, Santo André 09210-580, SP, Brazil.
  • Campeiro JD; Bluestar Genomics, San Diego, CA 92121, USA.
  • Machado-Neto JA; Department of Pharmacology, Federal University of São Paulo, São Paulo 04044-020, SP, Brazil.
  • Nascimento FD; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil.
  • Hayashi MAF; Interdisciplinary Center of Biochemistry Investigation, University of Mogi das Cruzes, Mogi das Cruzes 08780-911, SP, Brazil.
  • Tersariol ILS; Department of Molecular Biology, Federal University of São Paulo, São Paulo 04021-001, SP, Brazil.
  • Newmeyer DD; Department of Pharmacology, Federal University of São Paulo, São Paulo 04044-020, SP, Brazil.
  • Rodrigues T; Department of Molecular Biology, Federal University of São Paulo, São Paulo 04021-001, SP, Brazil.
Life (Basel) ; 12(10)2022 Sep 23.
Article em En | MEDLINE | ID: mdl-36294912
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Life (Basel) Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Brasil País de publicação: Suíça
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Life (Basel) Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Brasil País de publicação: Suíça