A Curcumin Derivative That Inhibits Vinyl Carbamate-Induced Lung Carcinogenesis via Activation of the Nrf2 Protective Response

Tao Shen, Tao Jiang, Min Long, Jun Chen, Dong Mei Ren, Pak Kin Wong, Eli Chapman, Bo Zhou, Donna D. Zhang

Research output: Contribution to journalArticle

35 Citations (Scopus)

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. Antioxid. Redox Signal. 23, 651-664.

Original languageEnglish (US)
Pages (from-to)651-664
Number of pages14
JournalAntioxidants and Redox Signaling
Volume23
Issue number8
DOIs
StatePublished - Sep 10 2015

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Curcumin
Carcinogenesis
Chemical activation
Derivatives
Lung
Lung Neoplasms
Toxicity
Epithelial Cells
Pharmacology
vinyl carbamate
Chemoprevention
Structure-Activity Relationship
Cytotoxicity
bis(2-hydroxybenzylidene)acetone
Carcinogens
Biological Availability
Oxidation-Reduction
Carbon
Innovation
Morbidity

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Shen, Tao ; Jiang, Tao ; Long, Min ; Chen, Jun ; Ren, Dong Mei ; Wong, Pak Kin ; Chapman, Eli ; Zhou, Bo ; Zhang, Donna D. / A Curcumin Derivative That Inhibits Vinyl Carbamate-Induced Lung Carcinogenesis via Activation of the Nrf2 Protective Response. In: Antioxidants and Redox Signaling. 2015 ; Vol. 23, No. 8. pp. 651-664.
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A Curcumin Derivative That Inhibits Vinyl Carbamate-Induced Lung Carcinogenesis via Activation of the Nrf2 Protective Response. / Shen, Tao; Jiang, Tao; Long, Min; Chen, Jun; Ren, Dong Mei; Wong, Pak Kin; Chapman, Eli; Zhou, Bo; Zhang, Donna D.

In: Antioxidants and Redox Signaling, Vol. 23, No. 8, 10.09.2015, p. 651-664.

Research output: Contribution to journalArticle

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T1 - A Curcumin Derivative That Inhibits Vinyl Carbamate-Induced Lung Carcinogenesis via Activation of the Nrf2 Protective Response

AU - Shen, Tao

AU - Jiang, Tao

AU - Long, Min

AU - Chen, Jun

AU - Ren, Dong Mei

AU - Wong, Pak Kin

AU - Chapman, Eli

AU - Zhou, Bo

AU - Zhang, Donna D.

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AB - 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. Antioxid. Redox Signal. 23, 651-664.

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