Tao Shen1,2, Tao Jiang1, Min Long3, Jun Chen4, Dong-Mei Ren2, Pak Kin Wong5, Eli Chapman1, Bo Zhou6, Donna D Zhang1,7. 1. 1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , Tucson, Arizona. 2. 2 Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University , Jinan, People's Republic of China . 3. 3 Department of Endocrinology, Xinqiao Hospital, Third Military Medical University , Chongqing, People's Republic of China . 4. 4 State Key Laboratory of Virology and Modern Virology Research Center, College of Life Sciences, Wuhan University , Wuhan, People's Republic of China . 5. 5 Department of Aerospace and Mechanical Engineering, University of Arizona , Tucson, Arizona. 6. 6 State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou, People's Republic of China . 7. 7 Arizona Cancer Center, University of Arizona , Tucson, Arizona.
Abstract
AIMS: 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. INNOVATION: 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. CONCLUSION: 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.
AIMS: 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. INNOVATION: 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. CONCLUSION: 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.
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