Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression.
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.
['Changchien|Jung-Jung|JJ|', 'Chen|Ying-Jung|YJ|', 'Huang|Chia-Hui|CH|', 'Cheng|Tian-Lu|TL|', 'Lin|Shinne-Ren|SR|', 'Chang|Long-Sen|LS|']
D000970:Antineoplastic Agents D017209:Apoptosis D002470:Cell Survival D004305:Dose-Response Relationship, Drug D015536:Down-Regulation D004789:Enzyme Activation D048049:Extracellular Signal-Regulated MAP Kinases D006801:Humans D020014:K562 Cells D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive D048369:MAP Kinase Kinase 1 D053078:Membrane Potential, Mitochondrial D008928:Mitochondria D047428:Protein Kinase Inhibitors D019253:Proto-Oncogene Proteins c-bcl-2 D016755:Proto-Oncogene Proteins c-jun D011796:Quinacrine D017382:Reactive Oxygen Species D015398:Signal Transduction D013997:Time Factors D014162:Transfection D051020:bcl-X Protein D048051:p38 Mitogen-Activated Protein Kinases
Quinacrine ERK ROS p38 MAPK BCL2 degradation BCL2L1 down-regulation