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  3. The design of 1,4-naphthoquinone derivatives and mechanisms underlying apoptosis induction through ROS-dependent MAPK/Akt/STAT3 pathways in human lung cancer cells

The design of 1,4-naphthoquinone derivatives and mechanisms underlying apoptosis induction through ROS-dependent MAPK/Akt/STAT3 pathways in human lung cancer cells

  • Bioorg Med Chem. 2019 Apr 15;27(8):1577-1587. doi: 10.1016/j.bmc.2019.03.002.
Yi Zhang 1,  Ying-Hua Luo 2,  Xian-Ji Piao 3,  Gui-Nan Shen 1,  Jia-Ru Wang 1,  Yu-Chao Feng 4,  Jin-Qian Li 1,  Wan-Ting Xu 1,  Yu Zhang 1,  Tong Zhang 1,  Chang-Yuan Wang 5,  Cheng-Hao Jin 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, China.
  • 2 College of Animal Science & Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, China.
  • 3 Department of Gynaecology and Obstetrics, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, Heilongjiang 163316, China.
  • 4 College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, China.
  • 5 College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, China. Electronic address: byndwcy@163.com.
  • 6 Department of Biochemistry and Molecular Biology, College of Life Science & Technology, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, China; College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, Heilongjiang 163319, China. Electronic address: jinchenghao3727@qq.com.
PMID: 30846406 DOI: 10.1016/j.bmc.2019.03.002
Abstract

The natural compound 1,4-naphthoquinone has potent anti-tumor activity. However, the clinical application of 1,4-naphthoquinone and its derivatives has been limited by their side effects. In this study, we attempted to reduce the toxicity of 1,4-naphthoquinone by synthesizing two derivatives: 2,3-dihydro-2,3-epoxy-2-propylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (EPDMNQ) and 2,3-dihydro-2,3-epoxy-2-nonylsulfonyl-5,8-dimethoxy-1,4-naphthoquinone (ENDMNQ). Then we evaluated the cytotoxicity and molecular mechanisms of these compounds in lung Cancer cells. EPDMNQ and ENDMNQ significantly inhibited the viabilities of three lung Cancer cell lines and induced A549 cell cycle arrest at the G1 phase. In addition, they induced the Apoptosis of A549 lung Cancer cells by increasing the phosphorylation of p38 and c-Jun N-terminal kinase (p-JNK), and decreasing the phosphorylation of extracellular signal-related kinase (p-ERK), protein kinase B (Akt), and signal transducer and activator of transcription 3 (STAT3). Furthermore, they increased Reactive Oxygen Species (ROS) levels in A549 cells; however, pretreatment with the ROS inhibitor N-acetyl-l-cysteine significantly inhibited EPDMNQ- and ENDMNQ-mediated Apoptosis and reversed apoptotic proteins expression. In conclusion, EPDMNQ and ENDMNQ induced G1 phase cell cycle arrest and Apoptosis in A549 cells via the ROS-mediated activation of mitogen activated protein kinase (MAPK), Akt and STAT3 signaling pathways.

Keywords

1,4-Naphthoquinone; Akt; Apoptosis; Lung cancer; MAPK; ROS; STAT3.

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