Larry H Bernstein, MD, Reporter & Curator
http://pharmaceuticalintelligence.com/2013/06/21/Nrf2 Role in Blocking DNA Damage/lhbern
DNA damage has been a central focus of carcinogenesis. The following is of great interest in this respect.
Nrf2 as a novel molecular target for chemoprevention.
Lee JS, Surh YJ.
Cancer Lett. 2005 Jun 28;224(2):171-84. Epub 2004 Nov 11.
Source
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea.
Abstract
One of the rational and effective strategies for chemoprevention is the blockade of DNA damage caused by carcinogenic insult. This can be achieved either
- by reducing the formation of reactive carcinogenic species
- or stimulating their detoxification.
A wide spectrum of xenobiotic metabolizing enzymes catalyze both phase I (oxidation and reduction) and phase II biotransformation (conjugation) reactions involved in carcinogen activation and/or deactivation. Several antioxidant-response element (ARE)-regulated gene products such as
- glutathione S-transferase,
- NAD(P)H:quinone oxidoreductase 1,
- UDP-glucuronosyltransferase,
- gamma-glutamate cysteine ligase, and
- hemeoxygenase-1
are known to mediate detoxification and/or to exert antioxidant functions thereby protecting cells from genotoxic damage.
The transcription of ARE-driven genes is regulated, at least in part,
- by nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2),
- which is sequestered in cytoplasm by Kelch-like ECH-associated protein 1 (Keap1).
Exposure of cells to ARE inducers results in
- the dissociation of Nrf2 from Keap1 and
- facilitates translocation of Nrf2 to the nucleus,
- where it heterodimerizes with small Maf protein, and
- binds to ARE,
eventually resulting in the transcriptional regulation of target genes.
The Nrf2-Keap1-ARE signaling pathway can be modulated by several upstream kinases including
- phosphatidylinositol 3-kinase,
- protein kinase C, and
- mitogen-activated protein kinases.
Selected Nrf2-Keap1-ARE activators, such as
- oltipraz,
- anethole dithiolethione,
- sulforaphane,
- 6-methylsulphinylhexyl isothiocyanate,
- curcumin,
- caffeic acid phenethyl ester,
- 4′-bromoflavone, etc.
are potential chemopreventive agents. This mini-review will focus on a chemopreventive strategy directed towards
- protection of DNA and other important cellular molecules by
- inducing de novo synthesis of phase II detoxifying or antioxidant genes via the Nrf2-ARE core signaling pathway.
Related articles
- Nrf2 Pathway Regulates Multidrug-Resistance-Associated Protein 1 in Small Cell Lung Cancer (plosone.org)
- antioxidant advancements (ericalawrencenaturopathy.wordpress.com)
- Proteomic Profiling Reveals That Resveratrol Inhibits HSP27 Expression and Sensitizes Breast Cancer Cells to Doxorubicin Therapy (plosone.org)
- LKB1 is a master kinase in cancer (pharmastrategyblog.com)
- Stopping Tumor Survival In Low-Oxygen Environments (medicalnewstoday.com)
English: Graph of Nrf2 publications (pubmed search) by year (Photo credit: Wikipedia)
Most lifespan influencing genes affect the rate of DNA damage (Photo credit: Wikipedia)
Single-strand and double-strand DNA damage (Photo credit: Wikipedia)
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