title: A Curcumin Derivative That Inhibits Vinyl Carbamate-Induced Lung Carcinogenesis via Activation of the Nrf2 Protective Response.
abstract: OBJECTIVE
  Lung cancer has a high worldwide morbidity and mortality. The employment of chemopreventive agents is effective to reduce lung cancer. Nuclear factor erythroid 2-related factor 2 (Nrf2) mitigates insults from both exogenous and endogenous sources and thus has been verified as a target for chemoprevention. Curcumin has long been recognized as a chemopreventive agent, but poor bioavailability and weak Nrf2 induction have prohibited clinical application. Thus, we have developed new curcumin derivatives and tested their Nrf2 induction.
  
  
  RESULTS
  Based on curcumin, we synthesized curcumin analogs with five carbon linkages and established a structure-activity relationship for Nrf2 induction. Among these derivatives, bis[2-hydroxybenzylidene]acetone (BHBA) was one of the most potent Nrf2 inducers with minimal toxicity and improved pharmacological properties and was thus selected for further investigation. BHBA activated the Nrf2 pathway in the canonical Keap1-Cys151-dependent manner. Furthermore, BHBA was able to protect human lung epithelial cells against sodium arsenite [As(III)]-induced cytotoxicity. More importantly, in an in vivo vinyl carbamate-induced lung cancer model in A/J mice, preadministration of BHBA significantly reduced lung adenocarcinoma, while curcumin failed to show any effects even at high doses.
  
  
  METHODS
  The curcumin derivative, BHBA, is a potent inducer of Nrf2. It was demonstrated to protect against As(III) toxicity in lung epithelial cells in an Nrf2-dependent manner. Furthermore, compared with curcumin, BHBA displayed improved chemopreventive activities in a carcinogen-induced lung cancer model.
  
  
  CONCLUSIONS
  Taken together, our results demonstrate that BHBA, a curcumin analog with improved Nrf2-activating and chemopreventive activities both in vitro and in vivo, could be developed into a chemoprotective pharmacological agent.
authors.affiliation: 1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , Tucson, Arizona.|2 Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University , Jinan, People's Republic of China .
authors.forename: Tao
authors.initials: T
authors.lastname: Shen
authors.affiliation: 1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , Tucson, Arizona.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: 3 Department of Endocrinology, Xinqiao Hospital, Third Military Medical University , Chongqing, People's Republic of China .
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.affiliation: 4 State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University , Wuhan, People's Republic of China .
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: 2 Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University , Jinan, People's Republic of China .
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Ren
authors.affiliation: 5 Department of Aerospace and Mechanical Engineering, University of Arizona , Tucson, Arizona.
authors.forename: Pak Kin
authors.initials: PK
authors.lastname: Wong
authors.affiliation: 1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , Tucson, Arizona.
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
authors.affiliation: 6 State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, People's Republic of China .
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: 1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , Tucson, Arizona.|7 Arizona Cancer Center, University of Arizona , Tucson, Arizona.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000096:Acetone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D018053:Arsenites / Q000378:metabolism; D001593:Benzyl Compounds / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000737:chemistry; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D017670:Sodium Compounds / Q000378:metabolism; D014520:Urethane / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D018053:Arsenites; D001593:Benzyl Compounds; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017670:Sodium Compounds; C518535:bis(2-hydroxybenzylidene)acetone; D000096:Acetone; D014520:Urethane; C017947:sodium arsenite; C017963:vinyl carbamate; D003474:Curcumin