title: Raf/MEK/ERK signaling inhibition enhances the ability of dequalinium to induce apoptosis in the human leukemic cell line K562.
abstract: Delocalized lipophilic cations, such as dequalinium (DQA), selectively accumulate in mitochondria and display anticancer activity in cells from different malignancies. Previous studies in K562 human leukemic cells indicate that DQA causes cell damage as a consequence of an early disturbance in the mitochondrial function, inducing oxidative stress. These cells turned out to be resistant to apoptosis and died by necrosis when treated with high DQA concentrations (20 μmol/L) for long time periods (48 h). Resistance of K562 cells to DQA-induced apoptosis could be eliminated by inhibition of the kinase activity of the Bcr-Abl protein with imatinib. In this paper, we have studied the effect of DQA on the Raf/MEK/ERK1/2 and PI3K/Akt signal transduction pathways in K562 cells. Our data suggest a DQA downregulatory activity on both ERK1/2 and PI3K protein kinase activity supporting an interaction between both proteins. Moreover, inhibition of ERK1/2 with U0126 enhanced the ability of DQA to potentiate imatinib-induced apoptosis, suggesting a role of the Raf/MEK/ERK pathway and the Bcr-Abl tyrosine kinase in the K562 cell survival. This study contributes to a better understanding of the action mechanism of DQA on K562 cells and encourages the study of DQA in combination with other agents for improving the efficacy of targeted therapies and overcoming resistance to chemotherapeutic agents.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Campus Universitario, Universidad de Alcalá, Madrid. pilar.sancho@uah.es
authors.forename: Pilar
authors.initials: P
authors.lastname: Sancho
authors.forename: Eva
authors.initials: E
authors.lastname: Galeano
authors.forename: María Cristina
authors.initials: MC
authors.lastname: Estañ
authors.forename: Irene
authors.initials: I
authors.lastname: Gañán-Gómez
authors.forename: María Del Carmen
authors.initials: Mdel C
authors.lastname: Boyano-Adánez
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: García-Pérez
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D003868:Dequalinium / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D003868:Dequalinium; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases