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

  • Thomas W. Kensler
  • Patricia A. Egner
  • Abena S. Agyeman
  • Kala Visvanathan
  • John D. Groopman
  • Jian-Guo Chen
  • Tao-Yang Chen
  • Jed W. Fahey
  • Paul Talalay
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 329)

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 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Thomas W. Kensler
    • 1
    • 2
    • 3
    • 4
  • Patricia A. Egner
    • 1
  • Abena S. Agyeman
    • 2
  • Kala Visvanathan
    • 5
  • John D. Groopman
    • 1
  • Jian-Guo Chen
    • 6
  • Tao-Yang Chen
    • 6
  • Jed W. Fahey
    • 3
  • Paul Talalay
    • 3
  1. 1.Department of Environmental Health SciencesJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  2. 2.Department of Biochemistry and Molecular BiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  3. 3.Department of Pharmacology and Molecular SciencesJohns Hopkins School of MedicineBaltimoreUSA
  4. 4.Department of Pharmacology & Chemical BiologyUniversity of PittsburghPittsburghUSA
  5. 5.Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  6. 6.Qidong Liver Cancer InstituteQidongPeople’s Republic of China

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