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Adaptive cytoprotection and cancer chemoprotection by sulforaphane against various stresses: role of nrf2‐keap1 dependent and independent pathways (1052.1)
Author(s) -
Yanaka Akinori
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1052.1
Subject(s) - sulforaphane , azoxymethane , cytoprotection , aberrant crypt foci , oxidative stress , keap1 , pharmacology , curcumin , celecoxib , apoptosis , chemistry , resveratrol , knockout mouse , cancer research , colorectal cancer , cancer , medicine , biochemistry , colonic disease , transcription factor , gene , receptor
Background and Aims: Mild irritants protect GI mucosa from more severe stress, called “adaptive cytoprotection”. Prostaglandins have been proposed as mediators for this phenomenon. In contrast, recent studies show that nrf2‐dependendent anti‐oxidant system may be responsible for this protection, since most of the physiological stresses are oxidative stress in GI tract. In this study, we examined if sulforaphane (SFN), a nrf2‐stimulating phytochemical rich in broccoli sprouts, protects GI mucosa against various physiological stresses. We also examined if SFN inhibits tumor formation in chemically induced colon cancer model in mice. Methods: 1. Adaptive Cytoprotection by SFN: 1)In vitro model for intestinal injury: IEC6 cells were exposed to aspirin with or without SFN. 2) In vivo model for indomethacin‐induced small intestinal ulcer. Mice were treated with indomethacin (IND) with or without SFN. 2. Chemoprotection by SFN: C57/BL6 mice, pretreated with a chemical carcinogen, azoxymethane, were fed for 8 weeks with or without sulforaphane glucosinolate (SGS). Number of aberrant crypt foci (ACF), a precancerous lesion, in colonic mucosa in each mice were counted. Results: 1. 1) Pretreatment with SFN up‐regulated antioxidant enzymes activity, and protected IEC cells from aspirin‐induced injury. 2) Dietary SGS protected small intestine from IND‐induced injury. These effects were mitigated by a HO‐1 inhibitor, and were abolished in nrf2‐gene knockout mice. 2. SGS suppressed formation of ACF in azoxymethane‐treated mice, effects accompanied by inhibition of the cell proliferation, and enhancement of the apoptosis. These effects were demonstrated in both nrf2+/+ and nrf2‐/‐ mice. Conclusions: 1. SFN affords adaptive cytoprotection of small intestine against NSAIDs‐induced oxidative stress via induction of the nrf2‐dependent anti‐oxidant enzymes. 2. SFN affords chemoprotection against colon cancer via nrf2‐independent mechanisms.