title: Dequalinium induces cytotoxicity in human leukemia NB4 cells by downregulation of Raf/MEK/ERK and PI3K/Akt signaling pathways and potentiation of specific inhibitors of these pathways.
abstract: Delocalized lipophilic cation dequalinium (DQA) selectively accumulates in mitochondria and displays anticancer activity in different malignancies. Our previous studies indicate a DQA-induced cytotoxicity in human acute promyelocytic leukemia NB4 cells by early disturbance in mitochondrial function and oxidative stress. This study shows the ability of DQA to downregulate Raf/MEK/ERK1/2 and PI3K/Akt signaling pathways in NB4 cells which leads to cell death by apoptosis and/or necrosis. Moreover, DQA potentiates the action of specific inhibitors of these pathways. These DQA effects could be mediated by redox regulation of Akt. Our results contribute to a better understanding of the cytotoxic DQA mechanism on leukemia cells and encourage the performance of further studies in combination with other agents such as kinase inhibitors for improving the efficacy of therapies against acute promyelocytic leukemia.
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain. Electronic address: ana.garcia@uah.es.
authors.forename: Ana I
authors.initials: AI
authors.lastname: García-Pérez
authors.affiliation: Centro de Investigación Médica Aplicada, Universidad de Navarra, Avda. Pío XII, 55, E-31008 Pamplona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Galeano
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Nieto
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Estañ
authors.affiliation: Departamento de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sancho
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D003868:Dequalinium / Q000494:pharmacology*; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D003868:Dequalinium; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases
keywords: Dequalinium; LY294002; Leukemia cells; NB4; PI3K/Akt; Raf/MEK/ERK; UO126