title: Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation.
abstract: A wide array of phenolic substances, particularly those present in edible and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Cyclooxygenase-2 (COX-2) inducible and nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. Improper up-regulation of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage. Examples are curcumin, a yellow pigment of turmeric (Curcuma longa L., Zingiberaceae), the green tea polyphenol epigallocatechin gallate (EGCG), and resveratrol from grapes (Vitis vinifera, Vitaceae) that strongly suppress tumor promotion. Recent studies have demonstrated that eukaryotic transcription factor nuclear factor-kappa B (NF-kappa B) is involved in regulation of COX-2 and iNOS expression. Several chemopreventive phytochemicals have been shown to inhibit COX-2 and iNOS expression by blocking improper NF-kappa B activation. Multiple lines of compelling evidence indicate that extracellular-regulated protein kinase and p38 mitogen-activated protein kinase are key elements of the intracellular signaling cascades responsible for NF-kappa B activation in response to a wide array of external stimuli. Curcumin, EGCG and resveratrol have been shown to suppress activation of NF-kappa B. One of the plausible mechanisms underlying inhibition of NF-kappa B activation by aforementioned phytochemicals involves repression of degradation of the inhibitory unit I kappa B alpha, which hampers subsequent nuclear translocation of the functionally active subunit of NF-kappa B.
authors.affiliation: College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea. surh@plaza.snu.ac.kr
authors.forename: Y J
authors.initials: YJ
authors.lastname: Surh
authors.forename: K S
authors.initials: KS
authors.lastname: Chun
authors.forename: H H
authors.initials: HH
authors.lastname: Cha
authors.forename: S S
authors.initials: SS
authors.lastname: Han
authors.forename: Y S
authors.initials: YS
authors.lastname: Keum
authors.forename: K K
authors.initials: KK
authors.lastname: Park
authors.forename: S S
authors.initials: SS
authors.lastname: Lee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D018890:Chemoprevention; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases