title: Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression.
abstract: Although previous studies have revealed the anti-cancer activity of quinacrine, its effect on leukemia is not clearly resolved. We sought to explore the cytotoxic effect and mechanism of quinacrine action in human leukemia K562 cells. Quinacrine induced K562 cell apoptosis accompanied with ROS generation, mitochondrial depolarization, and down-regulation of BCL2L1 and BCL2. Upon exposure to quinacrine, ROS-mediated p38 MAPK activation and ERK inactivation were observed in K562 cells. Quinacrine-induced cell death and mitochondrial depolarization were suppressed by the p38MAPK inhibitor SB202190 and constitutively active MEK1 over-expression. Activation of p38 MAPK was shown to promote BCL2 degradation. Further, ERK inactivation suppressed c-Jun-mediated transcriptional expression of BCL2L1. Over-expression of BCL2L1 and BCL2 attenuated quinacrine-evoked mitochondrial depolarization and rescued the viability of quinacrine-treated cells. Taken together, our data indicate that quinacrine-induced K562 cell apoptosis is mediated through mitochondrial alterations triggered by p38 MAPK-mediated BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression.
authors: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors: Jung-Jung
authors: JJ
authors: Changchien
authors: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors: Ying-Jung
authors: YJ
authors: Chen
authors: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors: Chia-Hui
authors: CH
authors: Huang
authors: Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Tian-Lu
authors: TL
authors: Cheng
authors: Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Shinne-Ren
authors: SR
authors: Lin
authors: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: lschang@mail.nsysu.edu.tw.
authors: Long-Sen
authors: LS
authors: Chang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011796:Quinacrine / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D011796:Quinacrine
keywords: BCL2 degradation; BCL2L1 down-regulation; ERK; Quinacrine; ROS; p38 MAPK