title: 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.
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.
authors.affiliation: Clinical Pharmacology Laboratory, Zhengzhou University People's Hospital, Zhengzhou, Henan, China.
authors.forename: Yong-Cheng
authors.initials: YC
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Department of Urology, University of California, Irvine, California, USA.|Department of Pharmacology, University of California, Irvine, California, USA.|Chao Family Comprehensive Cancer Center, University of California, Irvine, California, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zi
authors.affiliation: Clinical Pharmacology Laboratory, Zhengzhou University People's Hospital, Zhengzhou, Henan, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Clinical Pharmacology Laboratory, Zhengzhou University People's Hospital, Zhengzhou, Henan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Clinical Pharmacology Laboratory, Zhengzhou University People's Hospital, Zhengzhou, Henan, China.
authors.forename: Ying-Li
authors.initials: YL
authors.lastname: Zhu
authors.affiliation: Clinical Pharmacology Laboratory, Zhengzhou University People's Hospital, Zhengzhou, Henan, China.
authors.forename: Xia-Xia
authors.initials: XX
authors.lastname: Fan
authors.affiliation: Clinical Pharmacology Laboratory, Zhengzhou University People's Hospital, Zhengzhou, Henan, China.
authors.forename: Ning-Min
authors.initials: NM
authors.lastname: Zhao
authors.affiliation: Clinical Pharmacology Laboratory, Zhengzhou University People's Hospital, Zhengzhou, Henan, China.
authors.forename: Qiao-Yan
authors.initials: QY
authors.lastname: Li
authors.affiliation: Clinical Pharmacology Laboratory, Zhengzhou University People's Hospital, Zhengzhou, Henan, China.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Qin
authors.affiliation: School of Pharmaceutical Sciences and Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou University, Zhengzhou, China.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D045786:Diterpenes, Kaurane / Q000737:chemistry / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D045786:Diterpenes, Kaurane; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c
keywords: Bax; ROS; ent-kaurene diterpenoid derivative; esophageal squamous cell carcinoma; mitochondrion