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Natural Products in Cancer Prevention and Therapy

Volume 329 of the series Topics in Current Chemistry pp 163-177

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Keap1–Nrf2 Signaling: A Target for Cancer Prevention by Sulforaphane

  • Thomas W. KenslerAffiliated withDepartment of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public HealthDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public HealthDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of MedicineDepartment of Pharmacology & Chemical Biology, University of Pittsburgh Email author 
  • , Patricia A. EgnerAffiliated withDepartment of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health
  • , Abena S. AgyemanAffiliated withDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health
  • , Kala VisvanathanAffiliated withDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health
  • , John D. GroopmanAffiliated withDepartment of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health
  • , Jian-Guo ChenAffiliated withQidong Liver Cancer Institute
  • , Tao-Yang ChenAffiliated withQidong Liver Cancer Institute
  • , Jed W. FaheyAffiliated withDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
  • , Paul TalalayAffiliated withDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine

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Abstract

Sulforaphane is a promising agent under preclinical evaluation in many models of disease prevention. This bioactive phytochemical affects many molecular targets in cellular and animal models; however, amongst the most sensitive is Keap1, a key sensor for the adaptive stress response system regulated through the transcription factor Nrf2. Keap1 is a sulfhydryl-rich protein that represses Nrf2 signaling by facilitating the polyubiquitination of Nrf2, thereby enabling its subsequent proteasomal degradation. Interaction of sulforaphane with Keap1 disrupts this function and allows for nuclear accumulation of Nrf2 and activation of its transcriptional program. Enhanced transcription of Nrf2 target genes provokes a strong cytoprotective response that enhances resistance to carcinogenesis and other diseases mediated by exposures to electrophiles and oxidants. Clinical evaluation of sulforaphane has been largely conducted by utilizing preparations of broccoli or broccoli sprouts rich in either sulforaphane or its precursor form in plants, a stable β-thioglucose conjugate termed glucoraphanin. We have conducted a series of clinical trials in Qidong, China, a region where exposures to food- and air-borne carcinogens has been considerable, to evaluate the suitability of broccoli sprout beverages, rich in either glucoraphanin or sulforaphane or both, for their bioavailability, tolerability, and pharmacodynamic action in population-based interventions. Results from these clinical trials indicate that interventions with well characterized preparations of broccoli sprouts may enhance the detoxication of aflatoxins and air-borne toxins, which may in turn attenuate their associated health risks, including cancer, in exposed individuals.

Keywords

Sulforaphane Nrf2 chemoprevention DNA adducts mercapturic acids clinical trials