Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane

Abstract

With the properties of efficacy, safety, tolerability, practicability and low cost, foods containing bioactive phytochemicals are gaining significant attention as elements of chemoprevention strategies against cancer. Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane], a naturally occurring isothiocyanate produced by cruciferous vegetables such as broccoli, is found to be a highly promising chemoprevention agent against not only a variety of cancers such as breast, prostate, colon, skin, lung, stomach or bladder, but also cardiovascular disease, neurodegenerative diseases, and diabetes. For reasons of experimental exigency, preclinical studies have focused principally on sulforaphane itself, while clinical studies have relied on broccoli sprout preparations rich in either sulforaphane or its biogenic precursor, glucoraphanin. Substantive subsequent evaluation of sulforaphane pharmacokinetics and pharmacodynamics has been undertaken using either pure compound or food matrices. Sulforaphane affects multiple targets in cells. One key molecular mechanism of action for sulforaphane entails activation of the Nrf2-Keap1 signaling pathway although other actions contribute to the broad spectrum of efficacy in different animal models. This review summarizes the current status of pre-clinical chemoprevention studies with sulforaphane and highlights the progress and challenges for the application of foods rich in sulforaphane and/or glucoraphanin in the arena of clinical chemoprevention.

Keywords: Cancer; Chemoprevention; Nrf2; Sulforaphane.

Figure 1

Scheme of Keap1-Nrf2 interactions. Under homeostatic conditions, Nrf2 is bound by Keap1 through the “hinge” (ETGE) and “latch” (DLG) domains of Nrf2. Upon association, Nrf2 is ubiquitinated (Ub) by the Cul3 ubiquitin ligaase complex, marking it for proteasomal degradation. Induction of Nrf2 signaling by sulforaphane through thiocarbamylation at Cys151 (cysteine 151) may lead to disruption or perturbation of the Cul3 association with Keap1 and abrogation of Nrf2 ubiquitination. Newly synthesized Nrf2 thereby escapes proteasomal degradation and translocates to the nucleus where it accumulates and activates the transcription of its target genes. Target genes of Nrf2 include multiple isoforms of glutathione S-transferases (GSTs) which in turn can conjugate acrolein or metabolites of benzene, and polycyclic aromatic hydrocarbons leading to the excretion of these air pollutants in urine as mercapturic acids.

Figure 2

Glucoraphanin in broccoli is converted to sulforaphane either by plant myrosinases, or if the plant myrosinases have been denatured by cooking, by bacterial β-thioglucosidases in the human colon. Sulforaphane is passively absorbed and rapidly conjugated with glutathione by glutathione S-transferases (GSTs), then metabolized sequentially by γ-glutamyl-transpeptidase (GTP), cysteinyl-glycinease (GCase) and N-acetyltransferase (NAT). The conjugates are actively transported into the systemic circulation where the merapturic acid and its precursors are urinary excretion products. Deconjugation may also occur to yield the parent isothiocyanate, sulforaphane. The mercapturic acid and cysteine conjugate forms are the major urinary metabolites of sulforaphane.