Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair
Background and aims
Chronic inflammation, induced by biological, chemical, and physical factors, was associated with increased risk of human cancer at various sites. Chronic inflammatory processes induce oxidative/nitrosative stress and lipid peroxidation (LPO), thereby generating excess reactive oxygen species (ROS), reactive nitrogen species (RNS), and DNA-reactive aldehydes. Miscoding etheno- and propano-modified DNA bases are generated inter alia by reaction of DNA with these major LPO products. Steady-state levels of LPO-derived (etheno-) DNA adducts in organs affected by persistent inflammatory processes were investigated as potential lead markers for assessing progression of inflammatory cancer-prone diseases.
Using ultrasensitive and specific detection methods for the analysis of human tissues, cells, and urine, etheno-DNA adduct levels were found to be significantly elevated in the affected organs of subjects with chronic pancreatitis, ulcerative colitis, and Crohn’s disease. Patients with alcohol-related liver diseases showed excess hepatic DNA damage progressively increasing from hepatitis, fatty liver, to liver cirrhosis. Ethenodeoxyadenosine excreted after DNA repair in urine of hepatitis B virus-related chronic hepatitis and liver cirrhosis patients was increased up to 90-fold. Putative mechanisms that may control DNA damage in inflamed tissues including impaired or imbalanced DNA repair pathways are reviewed.
Persistent oxidative/nitrosative stress and excess LPO are induced by inflammatory processes in a self-perpetuating process and cause progressive accumulation of DNA damage in target organs. Together with deregulation of cell homeostasis, the resulting genetic changes act as driving force in chronic inflammation-associated human disease pathogenesis. Thus steady-state levels of DNA damage caused by ROS, RNS, and LPO end products provide promising molecular signatures for risk prediction and potential targets and biomarkers for preventive measures.
KeywordsChronic inflammation Oxidative stress DNA damage Impaired DNA repair Human cancers
- 2.Ohshima H, Bartsch H (1994) Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat Res 3005:253–264Google Scholar
- 10.Bartsch H (1999) Exocyclic adducts as new risk markers for DNA damage in man. In: Singer B, Bartsch H (eds) Exocyclic DNA adducts in mutagenesis and carcinogenesis, no. 150. IARC, Lyon, pp 1–16Google Scholar
- 19.Nair J (1999) Lipid peroxidation-induced etheno-DNA adducts in humans. In: Singer B, Bartsch H (eds) Exocyclic DNA adducts in mutagenesis and carcinogenesis, no. 150. IARC, Lyon, pp 55–62Google Scholar
- 20.Singer B, Bartsch H (eds) (1999) Exocyclic DNA adducts in mutagenesis and carcinogenesis, no. 150. IARC, Lyon, pp 55–62Google Scholar
- 26.Hanaoka T, Nair J, Takahashi Y, Sasaki S, Bartsch H, Tsugane S (2002) Urinary level of 1,N6-etheno-deoxyadenosine, a marker of oxidative stress, is associated with salt excretion and ω6-polyunsaturated fatty acid intake in postmenopausal Japanese women. Int J Cancer 100:71–75PubMedCrossRefGoogle Scholar
- 27.Sun X, Karlsson A, Bartsch H, Nair J (2006) A new ultrasensitive 32P-postlabeling method for the analysis of 3,N 4-etheno-2′-deoxycytidine in human urine. Biomarkers (in press)Google Scholar
- 28.Chen HJ, Chang CM (2004) Quantification of urinary excretion of 1,N6-ethenoadenine, a potential biomarker of lipid peroxidation, in humans by stable isotope dilution liquid chromatography–electrospray ionization-tandem mass spectrometry: comparison with gas chromatography-mass spectrometry. Chem Res Toxicol 17:963–971PubMedCrossRefGoogle Scholar
- 32.Leuratti C, Watson MA, Deag EJ, Welch A, Singh R, Gottschald E, Marnett LJ, Atkin W, Day NE, Shuker DE, Bingham SA (2002) Detection of malondialdehyde DNA adducts in human colorectal mucosa: relationship with diet and the presence of adenomas. Cancer Epidemiol Biomarkers Prev 11:267–273PubMedGoogle Scholar
- 44.Nair J, Srivatanakul P, Jedpiyawongse A, Bartsch H (2002) Urinary excretion of 1,N6-ethenodeoxyadenosine in patients diagnosed with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma from Thailand. Proc AACR 42:2843Google Scholar
- 48.Hussain SP, Raja K, Amstad PA, Sawyer M, Trudel LJ, Wogan GN, Hofseth LJ, Shields PG, Billiar TR, Trautwein C, Hohler T, Galle PR, Phillips DH, Markin R, Marrogi AJ, Harris CC (2000) Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis: oxyradical overload diseases. Proc Natl Acad Sci USA 97:12770–12775PubMedCrossRefGoogle Scholar
- 49.Hu W, Feng Z, Eveleigh J, Lyer G, Pan J, Amin S, Chung FT, Tang MS (2002) The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis 23:1781–1789PubMedCrossRefGoogle Scholar
- 56.Hussain SP, Amstad P, Raja K, Ambs S, Nagashima M, Bennett WP, Shields PG, Ham AJ, Swenberg JA, Marrogi AJ, Harris CC (2000) Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 60:333–337Google Scholar
- 57.Hofseth LJ, Khan MA, Ambrose M, Nikolayeva O, Xu-Welliver M, Kartalou M, Hussain SP, Roth RB, Zhou X, Mechanic LE, Zurer I, Rotter V, Samson LD, Harris CC (2004) The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation. J Clin Invest 113:490CrossRefGoogle Scholar
- 59.Iacopini F, Consolazio A, Bosco D, Marcheggiano A, Bella A, Pica R, Paoluzi OA, Crispino P, Rivera M, Mottolese M, Nardi F, Paoluzi P Oxidative damage of the gastric mucosa in Helicobacter pylori positive chronic atrophic and nonatrophic gastritis, before and after eradication. Helicobacter 8:503–512Google Scholar
- 61.Nair J, Strand S, Frank N, Knauft J, Wesch H, Galle PR, Bartsch H (2005) Apoptosis and age-dependant induction of nuclear and mitochondrial etheno-DNA adducts in Long–Evans cinnamon (LEC) rats: enhanced DNA damage by dietary curcumin upon copper accumulation. Carcinogenesis 26:1307–1315PubMedCrossRefGoogle Scholar
- 63.Jaiswal M, LaRusso NF, Gores GJ (2001) Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol 281:626–634Google Scholar
- 65.Jaiswal M, LaRusso NF, Nishioka N, Nakabeppu Y, Gores GJ (2001) Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide. Cancer Res 61:6399–6393Google Scholar
- 79.Ohshima H, Tazawa H, Sylla BS, Sawa T (2005) Prevention of human cancer by modulation of chronic inflammatory processes. Mutat Res 59:110–122Google Scholar