Oncotarget

Research Papers:

Induction of the mitochondria-mediated apoptosis in human esophageal cancer cells by DS2, a newly synthetic diterpenoid analog, is regulated by Bax and caused by generation of reactive oxygen species

Yong-Cheng Ma, Yu Ke, Xiaolin Zi, Fei Zhao, Lin Yuan, Ying-Li Zhu, Xia-Xia Fan, Ning-Min Zhao, Qiao-Yan Li, Yu-Hua Qin and Hong-Min Liu _

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Oncotarget. 2016; 7:86211-86224. https://doi.org/10.18632/oncotarget.13367

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Abstract

Yong-Cheng Ma1,*, Yu Ke2,*, Xiaolin Zi3,4,5, Fei Zhao1, Lin Yuan1, Ying-Li Zhu1, Xia-Xia Fan1, Ning-Min Zhao1, Qiao-Yan Li1, Yu-Hua Qin1, Hong-Min Liu2

1Clinical Pharmacology Laboratory, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China

2School of Pharmaceutical Sciences and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, China

3Department of Urology, University of California, Irvine, California, USA

4Department of Pharmacology, University of California, Irvine, California, USA

5Chao Family Comprehensive Cancer Center, University of California, Irvine, California, USA

*These authors contributed equally to this work

Correspondence to:

Yu-Hua Qin, email: [email protected]

Hong-Min Liu, email: [email protected]

Keywords: ent-kaurene diterpenoid derivative, esophageal squamous cell carcinoma, ROS, mitochondrion, Bax

Received: September 09, 2016     Accepted: October 27, 2016     Published: November 15, 2016

ABSTRACT

Ent-kaurane diterpene compounds have attracted considerable attention in recent years due to its antitumor, antibacterial, and antiviral activities. However, the clinical development of natural kaurane diterpenes, for example, oridonin for cancer therapy has been hampered by its relatively moderate potency, limited bioavailability. Herein, we report a newly synthetic analog of natural ent-kaurane diterpene, DS2, which exhibits significantly improved activity of antiproliferation against various cancer cell lines relative to oridonin. DS2 treatment triggers the mitochondria-mediated apoptosis and cell cycle arrest in human esophageal cancer cell lines (EC9706, EC109). Interestingly, normal human esophageal epithelial cells (HEECs) and normal human liver cells (HL-7702) are both significantly more resistant to the growth inhibition by DS2 compared with esophageal cancer cells. The DS2-induced apoptosis in EC9706 cells correlated with the drop of mitochondrial membrane potential (MMP), release of cytochrome c into the cytosol and activation of caspase-9 and -3. The induction of proapoptotic proteins p21 and Bax were also observed in DS2-treated cells. The DS2-induced apoptosis was significantly attenuated by knockdown of Bax proteins. Meanwhile, the DS2 treatment caused generation of reactive oxygen species (ROS) in human esophageal cancer cells, but not in HEECs, which was attenuated by pretreatment with ROS scavenger N-acetylcysteine (NAC). More interestingly, the antioxidants pretreatment completely attenuated DS2 mediated loss of the MMP and apoptosis, as well as Bax expression and growth inhibition. In conclusion, the present study reveals that the mitochondria-mediated cell death by DS2 is associated with Bax regulation and ROS generation, and understanding the function and mechanism of DS2 will help us to design better anti-cancer drugs.


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