Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression

Jung-Jung Changchien; Ying-Jung Chen; Chia-Hui Huang; Tian-Lu Cheng; Shinne-Ren Lin; Long-Sen Chang

doi:10.1016/j.taap.2015.02.005

Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression

Toxicol Appl Pharmacol. 2015 Apr 1;284(1):33-41. doi: 10.1016/j.taap.2015.02.005. Epub 2015 Feb 12.

Authors

Jung-Jung Changchien¹, Ying-Jung Chen¹, Chia-Hui Huang¹, Tian-Lu Cheng², Shinne-Ren Lin³, Long-Sen Chang⁴

Affiliations

¹ Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
² Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
³ Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
⁴ 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.

PMID: 25684043
DOI: 10.1016/j.taap.2015.02.005

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.

Keywords: BCL2 degradation; BCL2L1 down-regulation; ERK; Quinacrine; ROS; p38 MAPK.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Survival / drug effects
Dose-Response Relationship, Drug
Down-Regulation
Enzyme Activation
Extracellular Signal-Regulated MAP Kinases / metabolism*
Humans
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
MAP Kinase Kinase 1 / genetics
MAP Kinase Kinase 1 / metabolism
Membrane Potential, Mitochondrial / drug effects
Mitochondria / drug effects
Mitochondria / metabolism
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Proto-Oncogene Proteins c-jun / metabolism*
Quinacrine / pharmacology*
Reactive Oxygen Species / metabolism
Signal Transduction / drug effects*
Time Factors
Transfection
bcl-X Protein / genetics
bcl-X Protein / metabolism*
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

Antineoplastic Agents
BCL2 protein, human
BCL2L1 protein, human
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
Proto-Oncogene Proteins c-jun
Reactive Oxygen Species
bcl-X Protein
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase 1
Quinacrine