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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Role of Advanced Glycation End Products in Carcinogenesis and their Therapeutic Implications

Author(s): David Schröter and Annika Höhn*

Volume 24, Issue 44, 2018

Page: [5245 - 5251] Pages: 7

DOI: 10.2174/1381612825666190130145549

open access plus


Aging is one of the biggest risk factors for the major prevalent diseases such as cardiovascular diseases, neurodegeneration and cancer, but due to the complex and multifactorial nature of the aging process, the molecular mechanisms underlying age-related diseases are not yet fully understood. Research has been intensive in the last years aiming to characterize the pathophysiology of aging and develop therapies to fight age-related diseases. In this context advanced glycation end products (AGEs) have received attention. AGEs, when accumulated in tissues, significantly increase the level of inflammation in the body which has long been associated with the development of cancer. Here we discuss the classical settings promoting AGE formation, as well as reduction strategies, occurrence and relevance of AGEs in cancer tissues and the role of AGE-interaction with the receptor for advanced glycation end products (RAGE) in cancer initiation and progression.

Keywords: Advanced glycation end products, cancer, aging, inflammation, RAGE, cardiovascular diseases.

Andres R, Pozefsky T, Swerdloff RS, Tobin JD. Effect of aging on carbohydrate metabolism Adv Metab Disord 1970. 1(Suppl. 1): 1-,349
Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: A review. Diabetologia 2001; 44(2): 129-46.
Morimoto RI. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev 2008; 22(11): 1427-38.
Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive ability of an incident cohort of Parkinson’s patients in the UK. The CamPaIGN study. Brain 2004; 127(Pt 3): 550-60.
Aunan JR, Cho WC, Søreide K. The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks. Aging Dis 2017; 8(5): 628-42.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68(1): 7-30.
Steves CJ, Spector TD, Jackson SH. Ageing, genes, environment and epigenetics: what twin studies tell us now, and in the future. Age Ageing 2012; 41(5): 581-6.
Strehler BL. Environmental factors in aging and mortality. Environ Res 1967; 1(1): 46-88.
vB Hjelmborg J, Iachine I, Skytthe A, et al. Genetic influence on human lifespan and longevity. Hum Genet 2006; 119: 312-21.
Simm A, Müller B, Nass N, et al. Protein glycation - Between tissue aging and protection. Exp Gerontol 2015; 68: 71-5.
Höhn A, König J, Grune T. Protein oxidation in aging and the removal of oxidized proteins. J Proteomics 2013; 92: 132-59.
Baynes JW. The Maillard hypothesis on aging: time to focus on DNA. Ann N Y Acad Sci 2002; 959: 360-7.
Simm A, Wagner J, Gursinsky T, et al. Advanced glycation endproducts: A biomarker for age as an outcome predictor after cardiac surgery? Exp Gerontol 2007; 42(7): 668-75.
Dyer DG, Dunn JA, Thorpe SR, Lyons TJ, McCance DR, Baynes JW. Accumulation of Maillard reaction products in skin collagen in diabetes and aging. Ann N Y Acad Sci 1992; 663: 421-2.
Verzijl N, DeGroot J, Oldehinkel E, et al. Age-related accumulation of Maillard reaction products in human articular cartilage collagen. Biochem J 2000; 350(Pt 2): 381-7.
Perrone L, Grant WB. Observational and ecological studies of dietary advanced glycation end products in national diets and Alzheimer’s disease incidence and prevalence. J Alzheimers Dis 2015; 45(3): 965-79.
Zimmerman GA, Meistrell M III, Bloom O, et al. Neurotoxicity of advanced glycation endproducts during focal stroke and neuroprotective effects of aminoguanidine. Proc Natl Acad Sci USA 1995; 92(9): 3744-8.
Yamagishi S, Ueda S, Okuda S. Food-derived advanced glycation end products (AGEs): A novel therapeutic target for various disorders. Curr Pharm Des 2007; 13(27): 2832-6.
Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A. Role of advanced glycation end products in cellular signaling. Redox Biol 2014; 2: 411-29.
Zinger A, Cho WC, Ben-Yehuda A. Cancer and Aging - the Inflammatory Connection. Aging Dis 2017; 8(5): 611-27.
Warburg O. The metabolism of carcinoma cells. J Cancer Res 1925; 9(1): 148-63.
Vistoli G, De Maddis D, Cipak A, Zarkovic N, Carini M, Aldini G. Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): An overview of their mechanisms of formation. Free Radic Res 2013; 47(Suppl. 1): 3-27.
Henning C, Glomb MA. Pathways of the Maillard reaction under physiological conditions. Glycoconj J 2016; 33(4): 499-512.
Hodge JE, Rist CE. The Amadori Rearrangement under New Conditions and its Significance for Non-enzymatic Browning Reactions2. J Am Chem Soc 1953; 75: 316-22.
Namiki M. Chemistry of Maillard reactions: recent studies on the browning reaction mechanism and the development of antioxidants and mutagens. Elsevier 1988; pp. 115-84.
Wolff SP, Dean RT. Glucose autoxidation and protein modification. The potential role of ‘autoxidative glycosylation’ in diabetes. Biochem J 1987; 245(1): 243-50.
Hamada Y, Araki N, Koh N, Nakamura J, Horiuchi S, Hotta N. Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway. Biochem Biophys Res Commun 1996; 228(2): 539-43.
Thornalley PJ. Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification--a role in pathogenesis and antiproliferative chemotherapy. Gen Pharmacol 1996; 27(4): 565-73.
Bucala R, Makita Z, Koschinsky T, Cerami A, Vlassara H. Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci USA 1993; 90(14): 6434-8.
Münch G, Schicktanz D, Behme A, et al. Amino acid specificity of glycation and protein-AGE crosslinking reactivities determined with a dipeptide SPOT library. Nat Biotechnol 1999; 17(10): 1006-10.
Luevano-Contreras C, Chapman-Novakofski K. Dietary advanced glycation end products and aging. Nutrients 2010; 2(12): 1247-65.
Uribarri J, Cai W, Peppa M, et al. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J Gerontol A Biol Sci Med Sci 2007; 62(4): 427-33.
Vlassara H, Cai W, Crandall J, et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci USA 2002; 99(24): 15596-601.
Vlassara H, Cai W, Tripp E, et al. Oral AGE restriction ameliorates insulin resistance in obese individuals with the metabolic syndrome: A randomised controlled trial. Diabetologia 2016; 59(10): 2181-92.
van Heijst JW, Niessen HW, Hoekman K, Schalkwijk CG. Advanced glycation end products in human cancer tissues: detection of Nepsilon-(carboxymethyl)lysine and argpyrimidine. Ann N Y Acad Sci 2005; 1043: 725-33.
Negre-Salvayre A, Coatrieux C, Ingueneau C, Salvayre R. Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br J Pharmacol 2008; 153(1): 6-20.
Uribarri J, Peppa M, Cai W, et al. Restriction of dietary glycotoxins reduces excessive advanced glycation end products in renal failure patients. J Am Soc Nephrol 2003; 14(3): 728-31.
Scheijen JLJM, Clevers E, Engelen L, et al. Analysis of advanced glycation endproducts in selected food items by ultra-performance liquid chromatography tandem mass spectrometry: Presentation of a dietary AGE database. Food Chem 2016; 190: 1145-50.
Niquet-Léridon C, Tessier FJ. Quantification of Nε-carboxymethyl-lysine in selected chocolate-flavoured drink mixes using high-performance liquid chromatography–linear ion trap tandem mass spectrometry. Food Chem 2011; 126: 655-63.
Rabbani N, Thornalley PJ. Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease. Biochem Biophys Res Commun 2015; 458(2): 221-6.
Dhar A, Desai K, Liu J, Wu L. Methylglyoxal, protein binding and biological samples: Are we getting the true measure? J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877(11-12): 1093-100.
Lapolla A, Reitano R, Seraglia R, Sartore G, Ragazzi E, Traldi P. Evaluation of advanced glycation end products and carbonyl compounds in patients with different conditions of oxidative stress. Mol Nutr Food Res 2005; 49(7): 685-90.
McLellan AC, Phillips SA, Thornalley PJ. The assay of methylglyoxal in biological systems by derivatization with 1,2-diamino-4,5-dimethoxybenzene. Anal Biochem 1992; 206(1): 17-23.
Chaplen FW, Fahl WE, Cameron DC. Evidence of high levels of methylglyoxal in cultured Chinese hamster ovary cells. Proc Natl Acad Sci USA 1998; 95(10): 5533-8.
Henle T. AGEs in foods: do they play a role in uremia? Kidney Int Suppl 2003; 63(84): S145-7.
Negre-Salvayre A, Salvayre R, Augé N, Pamplona R, Portero-Otin M. Hyperglycemia and glycation in diabetic complications Antioxidants & redox signaling 2009; 11: 3071-109.
Park MS, Lee HA, Chu WS, Yang DH, Hwang SD. Peritoneal accumulation of AGE and peritoneal membrane permeability. Perit Dial Int 2000; 20(4): 452-60.
Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 2014; 18(1): 1-14.
Goldberg T, Cai W, Peppa M, et al. Advanced glycoxidation end products in commonly consumed foods. J Am Diet Assoc 2004; 104(8): 1287-91.
Piroddi M, Palazzetti I, Quintaliani G, et al. Circulating levels and dietary intake of the advanced glycation end-product marker carboxymethyl lysine in chronic kidney disease patients on conservative predialysis therapy: A pilot study. J Ren Nutr 2011; 21(4): 329-39.
Uribarri J, Woodruff S, Goodman S, et al. Advanced glycation end products in foods and a practical guide to their reduction in the diet Journal of the American Dietetic Association 2010. 110: 911-6. e12
Koschinsky T, He C-J, Mitsuhashi T, et al. Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci USA 1997; 94(12): 6474-9.
Allavena P, Garlanda C, Borrello MG, Sica A, Mantovani A. Pathways connecting inflammation and cancer. Curr Opin Genet Dev 2008; 18(1): 3-10.
Förster A, Kühne Y, Henle T. Studies on absorption and elimination of dietary maillard reaction products. Ann N Y Acad Sci 2005; 1043: 474-81.
Hellwig M, Geissler S, Peto A, Knütter I, Brandsch M, Henle T. Transport of free and peptide-bound pyrraline at intestinal and renal epithelial cells. J Agric Food Chem 2009; 57(14): 6474-80.
Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest 2001; 108(7): 949-55.
Rojas A, Delgado-López F, González I, Pérez-Castro R, Romero J, Rojas I. The receptor for advanced glycation end-products: A complex signaling scenario for a promiscuous receptor. Cell Signal 2013; 25(3): 609-14.
Ishihara K, Tsutsumi K, Kawane S, Nakajima M, Kasaoka T. The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site. FEBS Lett 2003; 550(1-3): 107-13.
Hudson BI, Kalea AZ, Del Mar Arriero M, et al. Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem 2008; 283(49): 34457-68.
Origlia N, Righi M, Capsoni S, et al. Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. J Neurosci 2008; 28(13): 3521-30.
Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 2001; 280(5): E685-94.
Grimm S, Ott C, Hörlacher M, Weber D, Höhn A, Grune T. Advanced-glycation-end-product-induced formation of immunoproteasomes: involvement of RAGE and Jak2/STAT1. Biochem J 2012; 448(1): 127-39.
Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY. Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. J Cell Biochem 2001; 81(1): 102-13.
Yan SD, Schmidt AM, Anderson GM, et al. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 1994; 269(13): 9889-97.
Brownlee M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med 1995; 46: 223-34.
Lin L, Park S, Lakatta EG. RAGE signaling in inflammation and arterial aging. Front Biosci 2009; 14: 1403-13.
Andrassy M, Igwe J, Autschbach F, et al. Posttranslationally modified proteins as mediators of sustained intestinal inflammation. Am J Pathol 2006; 169(4): 1223-37.
Heidland A, Sebekova K, Schinzel R. Advanced glycation end products and the progressive course of renal disease. Am J Kidney Dis 2001; 38(4)(Suppl. 1): S100-6.
Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001; 357(9255): 539-45.
Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006; 441(7092): 431-6.
Grivennikov SI, Karin M. Inflammation and oncogenesis: A vicious connection. Curr Opin Genet Dev 2010; 20(1): 65-71.
Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag 2006; 2(3): 213-9.
DeNardo DG, Johansson M, Coussens LM. Immune cells as mediators of solid tumor metastasis. Cancer Metastasis Rev 2008; 27(1): 11-8.
Nguyen AH, Detty SQ, Agrawal DK. Clinical Implications of High-mobility Group Box-1 (HMGB1) and the Receptor for Advanced Glycation End-products (RAGE) in Cutaneous Malignancy: A Systematic Review. Anticancer Res 2017; 37(1): 1-7.
Nguyen AH, Bhavsar SB, Riley EM, Caponetti GC, Agrawal DK. Association of high mobility group BOX-1 and receptor for advanced glycation endproducts with clinicopathological features of haematological malignancies: A systematic review. Contemp Oncol (Pozn) 2016; 20(6): 425-9.
Zhao DC, Lu HW, Huang ZH. Association between the receptor for advanced glycation end products gene polymorphisms and cancer risk: A systematic review and meta-analysis. J BUON 2015; 20(2): 614-24.
Takino J, Nagamine K, Hori T, Sakasai-Sakai A, Takeuchi M. Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma. World J Hepatol 2015; 7(23): 2459-69.
Ishiguro H, Nakaigawa N, Miyoshi Y, Fujinami K, Kubota Y, Uemura H. Receptor for advanced glycation end products (RAGE) and its ligand, amphoterin are overexpressed and associated with prostate cancer development. Prostate 2005; 64(1): 92-100.
Rodriguez-Teja M, Gronau JH, Breit C, et al. AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival. J Pathol 2015; 235(4): 581-92.
Sharaf H, Matou-Nasri S, Wang Q, et al. Advanced glycation endproducts increase proliferation, migration and invasion of the breast cancer cell line MDA-MB-231. Biochim Biophys Acta 2015; 1852(3): 429-41.
Nankali M, Karimi J, Goodarzi MT, et al. Increased Expression of the Receptor for Advanced Glycation End-Products (RAGE) Is Associated with Advanced Breast Cancer Stage. Oncol Res Treat 2016; 39(10): 622-8.
Rahimi F, Karimi J, Goodarzi MT, et al. Overexpression of receptor for advanced glycation end products (RAGE) in ovarian cancer. Cancer Biomark 2017; 18(1): 61-8.
Kang R, Loux T, Tang D, et al. The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proc Natl Acad Sci USA 2012; 109(18): 7031-6.
Ben Q, Xu M, Ning X, et al. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. Eur J Cancer 2011; 47(13): 1928-37.
Zechner D, Radecke T, Amme J, et al. Impact of diabetes type II and chronic inflammation on pancreatic cancer. BMC Cancer 2015; 15: 51.
Menini S, Iacobini C, de Latouliere L, et al. The advanced glycation end-product Nϵ -carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes-associated risk and its prevention. J Pathol 2018; 245(2): 197-208.
Lopez-Moreno J, Quintana-Navarro GM, Delgado-Lista J, et al. Mediterranean Diet Reduces Serum Advanced Glycation End Products and Increases Antioxidant Defenses in Elderly Adults: A Randomized Controlled Trial. J Am Geriatr Soc 2016; 64(4): 901-4.
Harris CS, Cuerrier A, Lamont E, et al. Investigating wild berries as a dietary approach to reducing the formation of advanced glycation endproducts: chemical correlates of in vitro antiglycation activity. Plant Foods Hum Nutr 2014; 69(1): 71-7.
Vauzour D, Rodriguez-Mateos A, Corona G, Oruna-Concha MJ, Spencer JP. Polyphenols and human health: prevention of disease and mechanisms of action. Nutrients 2010; 2(11): 1106-31.
Aldini G, Vistoli G, Stefek M, et al. Molecular strategies to prevent, inhibit, and degrade advanced glycoxidation and advanced lipoxidation end products. Free Radic Res 2013; 47(Suppl. 1): 93-137.
Palimeri S, Palioura E, Diamanti-Kandarakis E. Current perspectives on the health risks associated with the consumption of advanced glycation end products: recommendations for dietary management. Diabetes Metab Syndr Obes 2015; 8: 415-26.
Coughlan MT, Forbes JM, Cooper ME. Role of the AGE crosslink breaker, alagebrium, as a renoprotective agent in diabetes. Kidney Int Suppl 2007; 72(106): S54-60.
Ueda S, Yamagishi S, Takeuchi M, et al. Oral adsorbent AST-120 decreases serum levels of AGEs in patients with chronic renal failure. Mol Med 2006; 12(7-8): 180-4.
Vlassara H, Li YM, Imani F, et al. Identification of galectin-3 as a high-affinity binding protein for advanced glycation end products (AGE): A new member of the AGE-receptor complex. Mol Med 1995; 1(6): 634-46.
Yamagishi S, Nakamura K, Matsui T, Ueda S, Fukami K, Okuda S. Agents that block advanced glycation end product (AGE)-RAGE (receptor for AGEs)-oxidative stress system: A novel therapeutic strategy for diabetic vascular complications. Expert Opin Investig Drugs 2008; 17(7): 983-96.
Chen Y, Filipov NM, Guo TL. Dietary Glycation Products Regulate Immune Homeostasis: Early Glycation Products Promote Prostate Cancer Cell Proliferation through Modulating Macrophages. Mol Nutr Food Res 2018; 62(3): 1700641.
Kong SY, Takeuchi M, Hyogo H, et al. The association between glyceraldehyde-derived advanced glycation end-products and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2015; 24(12): 1855-63.
Turner DP. Advanced glycation end-products: A biological consequence of lifestyle contributing to cancer disparity. Cancer Res 2015; 75(10): 1925-9.
Tantalaki E, Piperi C, Livadas S, et al. Impact of dietary modification of advanced glycation end products (AGEs) on the hormonal and metabolic profile of women with polycystic ovary syndrome (PCOS). Hormones (Athens) 2014; 13(1): 65-73.
Nowotny K, Jung T, Höhn A, Weber D, Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015; 5(1): 194-222.
Tesarova P, Cabinakova M, Mikulova V, Zima T, Kalousova M. RAGE and its ligands in cancer - culprits, biomarkers, or therapeutic targets? Neoplasma 2015; 62(3): 353-64.

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