KEAP1 and done? Targeting the NRF2 pathway with sulforaphane

Abstract

BackgroundSince the re-discovery of sulforaphane in 1992 and the recognition of the bioactivity of this phytochemical, many studies have examined its mode of action in cells, animals and humans. Broccoli, especially as young sprouts, is a rich source of sulforaphane and broccoli-based preparations are now used in clinical studies probing efficacy in health preservation and disease mitigation. Many putative cellular targets are affected by sulforaphane although only one, KEAP1-NRF2 signaling, can be considered a validated target at this time. The transcription factor NRF2 is a master regulator of cell survival responses to endogenous and exogenous stressors.Scope and ApproachThis review summarizes the chemical biology of sulforaphane as an inducer of NRF2 signaling and efficacy as an inhibitor of carcinogenesis. It also provides a summary of the current findings from clinical trials using a suite of broccoli sprout preparations on a series of short-term endpoints reflecting a diversity of molecular actions.Key Findings and ConclusionsSulforaphane, as a pure chemical, protects against chemical-induced skin, oral, stomach, colon, lung and bladder carcinogenesis and in genetic models of colon and prostate carcinogenesis. In many of these settings the antitumorigenic efficacy of sulforaphane is dampened in Nrf2-disrupted animals. Broccoli preparations rich in glucoraphanin or sulforaphane exert demonstrable pharmacodynamic action in over a score of clinical trials. Measures of NRF2 pathway response and function are serving as guideposts for the optimization of dose, schedule and formulation as clinical trials with broccoli-based preparations become more commonplace and more rigorous in design and implementation.

Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling

“…It has been reported that SFN can combat cancer by multiple mechanisms, including induce Nrf2 activation [36], epigenetic modulation of oncogenic MicroRNA-21 and human telomerase reverse transcriptase (hTERT) [37], inhibition of histone deacetylase (HDAC) [38] and NF-κB [39]. However, its anti-tumor effect on pancreatic cancer, especially under high glucose conditions, has not been investigated.…”

Nitro-fatty acids: New drug candidates for chronic inflammatory and fibrotic diseases

“…Aflatoxin is activated in the liver and alkylates cellular components, inducing mutations and cancer development (59). Electrophilic drugs targeting activation of Nrf2 induce the expression of over 100 Phase 2 genes, thus allowing for more efficient detoxification of aflatoxin and protection against carcinogenesis (60,61). In this regard, Evgen Pharma has now successfully stabilized sulforaphane using an α-cyclodextrin-based formulation, a key step towards the evaluation of sulforaphane in clinical trials.…”

Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot Study

“…Because of its presence in consumable food, sulforaphane is an attractive candidate for further human study. Indeed, its potential utility has been demonstrated in the treatment of asthma, air pollution injury, benign prostate hyperplasia, UV-induced erythema, diabetes, the control of Helicobacter pylori (a stomach carcinogen), and potentially in the prevention of a number of different cancers [42-44]. Furthermore, recent reports have suggested that administration of sulforaphane leads to beneficial outcomes of human brain disorders such as autism and SZ [45-47].…”