The newly synthesized 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one triggers cell apoptosis through induction of oxidative stress and upregulation of the p38 MAPK signaling pathway in HL-60 human leukemia cells

Cheng,Yung-Yi; Yang,Jai-Sing; Tsai,Shih-Chang; Liaw,Chih-Chuang; Chung,Jing-Gung; Huang,Li-Jiau; Lee,Kuo-Hsiung; Lu,Chi-Cheng; Chien,Hsi-Cheng; Tsuzuki,Minoru; Kuo,Sheng-Chu

doi:10.3892/or.2012.1923

The newly synthesized 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one triggers cell apoptosis through induction of oxidative stress and upregulation of the p38 MAPK signaling pathway in HL-60 human leukemia cells

Authors:
- Yung-Yi Cheng
- Jai-Sing Yang
- Shih-Chang Tsai
- Chih-Chuang Liaw
- Jing-Gung Chung
- Li-Jiau Huang
- Kuo-Hsiung Lee
- Chi-Cheng Lu
- Hsi-Cheng Chien
- Minoru Tsuzuki
- Sheng-Chu Kuo
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Affiliations: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 404, Taiwan, R.O.C., Department of Pharmacology, China Medical University, Taichung 404, Taiwan, R.O.C., Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, R.O.C., Department of Marine Biotechnology and Resource, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, R.O.C., Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA, Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan, R.O.C., Tsuzuki Institute for Traditional Medicine, China Medical University, Taichung 404, Taiwan, R.O.C.
Published online on: July 19, 2012 https://doi.org/10.3892/or.2012.1923
Pages: 1482-1490

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Abstract

The aim of the present study was to discover the signaling pathways associated with 2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one (YYK1)-induced apoptosis in HL-60 human leukemia cells. YYK1 induced cytotoxic effects, cell morphological changes, decreased the cell number and increased reactive oxygen species (ROS) production and loss of mitochondrial membrane potential (ΔΨm) in HL-60 cells. YYK1-induced apoptosis was confirmed by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Results from colorimetric assays and western blot analysis indicated that activities of caspase-7/-3, caspase-8 and caspase-9 were increased in YYK1-treated HL-60 cells. Western blot analysis showed that the protein levels of extrinsic apoptotic proteins (Fas/CD95, FasL and FADD), intrinsic related proteins (cytochrome c, Apaf-1, AIF and Endo G), the ratio of Bax/Bcl-2 and phosphorylated p38 MAPK were increased in HL-60 cells after YYK1 treatment. Cell apoptosis was significantly reduced after pre-treatment with N-acetylcysteine (NAC; a ROS scavenger) or diphenyleneiodonium chloride (DPI; a NADPH oxidase inhibitor). Blockage of p38 MAPK signaling by SB202190 abolished YYK1-induced Fas/CD95 upregulation and apoptosis in HL-60 cells. We conclude that YYK1 induces both of extrinsic and intrinsic apoptotic pathways via ROS-mediated activation of p38 MAPK signaling in HL-60 human leukemia cells in vitro.

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