title: Pro-Apoptotic Effects of JDA-202, a Novel Natural Diterpenoid, on Esophageal Cancer Through Targeting Peroxiredoxin I.
abstract: Esophageal cancer (EC) is an aggressive malignancy and the most common solid tumor of gastrointestinal tract all over the world, with high incidence in Asia. The current study was designed to investigate the anticancer efficacy and mechanism that is involved in the action of a natural ent-kaurene diterpenoid, JDA-202, targeting EC.
  
  
  
  We found that an antioxidant protein peroxiredoxin I (Prx I) was upregulated in human EC tissues as well as in EC cell lines. JDA-202, a novel natural compound isolated from Isodon rubescens (Labiatae), was proved to possess strong anti-proliferative activities on those cell lines. Importantly, JDA-202 does not only bind to Prx I directly and markedly inhibit the activity of Prx I in vitro, but it also significantly induces hydrogen peroxide (H2O2)-related cell death. Furthermore, overexpression of Prx I significantly reversed EC109 cell apoptosis caused by JDA-202, whereas short interfering RNA (siRNA)-induced Prx I knockdown resulted in marked cell death even without JDA-202 pretreatment. On the other hand, the increased phosphorylation of mitogen-activated protein kinase (MAPK) proteins (c-Jun N-terminal kinase [JNK], p38, and extracellular signal-regulated kinase [ERK]) by JDA-202 was suppressed by N-acetylcysteine (NAC) or catalase, a known reactive oxygen species (ROS) or H2O2scavenger. JDA-202 also significantly inhibited the growth of EC109 tumor xenograft, without significant body weight loss and multi-organ toxicities. Innovation and Conclusion: Our findings, for the first time, demonstrated that JDA-202 may serve as a lead compound, targeting the overexpressed Prx I in EC cell lines and ROS accumulation as well as inhibiting the activation of their downstream targets in MAPKs. Antioxid. Redox Signal. 27, 73-92.
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Shi
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Lina
authors.initials: L
authors.lastname: Ding
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Yage
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Junwei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Huimin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Guozhong
authors.initials: G
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Kai
authors.initials: K
authors.lastname: Tang
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Yu
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-Innovation Center of Henan Province for New Drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, Zhengzhou University , Zhengzhou, China .
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Liu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000008:administration & dosage* / Q000494:pharmacology; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D037602:Isodon / Q000737:chemistry*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D023041:Xenograft Model Antitumor Assays
chemical_list: D045786:Diterpenes, Kaurane; D004365:Drugs, Chinese Herbal; D006861:Hydrogen Peroxide; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; D020928:Mitogen-Activated Protein Kinases
keywords: EC; H2O2; JDA-202; Prx I