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Systemic Iron Supplementation Replenishes Iron Stores Without Enhancing Colon Carcinogenesis in Murine Models of Ulcerative Colitis: Comparison with Iron-Enriched Diet

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Abstract

Ulcerative colitis (UC) patients frequently require iron supplementation to remedy anemia. The impact of systemic iron supplementation (intraperitoneal injection) on UC-associated carcinogenesis was assessed in mice subjected to cyclic dextran sulfate sodium (DSS) treatment and compared with dietary iron enrichment. Systemic iron supplementation, but not a twofold iron diet, remedied iron deficiency as indicated by the histochemical detection of splenic iron stores. A twofold iron diet, but not systemic iron, increased iron accumulation in colonic luminal contents, at the colonic mucosal surface, and in superficial epithelial cells. Colitis-associated colorectal tumor incidence after 15 DSS cycles was not affected by systemic iron (2/28; 7.1%) compared to nonsupplemented controls (4/28; 14.1%) but was significantly increased by the twofold iron diet (24/33; 72.7%) (P < 0.001). Mechanistic study revealed that systemic iron had no effect on DSS-induced inflammation, or colonic iNOS and COX-2 protein levels, compared to controls. Systemic iron supplementation for 16 weeks replenished splenic iron in a spontaneous colitis model (interleukin-2-deficient mice) and significantly reduced colonic inflammation compared to interleukin-2 (−/−) controls without increasing hyperplastic lesions. These results suggest that iron supplemented systemically could be used to remedy anemia in UC patients without exacerbating inflammation or enhancing colon cancer risk. These findings need to be verified in clinical studies.

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References

  1. Fiocchi C: Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115:182–205, 1998

    CAS  PubMed  Google Scholar 

  2. Farrell RJ, Peppercorn MA: Ulcerative colitis. Lancet 359:331–340, 2002

    PubMed  Google Scholar 

  3. Wilson A, Reyes E, Ofman J: Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am J Med 116(Suppl 7A):44S–49S, 2004

    PubMed  Google Scholar 

  4. Truelove SC: Medical management of ulcerative colitis. Br Med J 2:605–607, 1968

    PubMed  CAS  Google Scholar 

  5. Barrison IG, Roberts PD, Kane SP: Oral or parenteral iron treatment in chronic ulcerative colitis? Br Med J (Clin Res Ed) 282: 1514, 1981

    Article  CAS  Google Scholar 

  6. Pietrangelo A: Physiology of iron transport and the hemochromatosis gene. Am J Physiol Gastrointest Liver Physiol 282:G403–G414, 2002

    PubMed  CAS  Google Scholar 

  7. Knutson M, Wessling-Resnick M: Iron metabolism in the reticuloendothelial system. Crit Rev Biochem Mol Biol 38:61–88, 2003

    PubMed  CAS  Google Scholar 

  8. Burns DL, Mascioli EA, Bistrian BR: Parenteral iron dextran therapy: a review. Nutrition 11:163–168, 1995

    PubMed  CAS  Google Scholar 

  9. Reifen R, Matas Z, Zeidel L, Berkovitch Z, Bujanover Y: Iron supplementation may aggravate inflammatory status of colitis in a rat model. Dig Dis Sci 45:394–397, 2000

    PubMed  CAS  Google Scholar 

  10. Carrier J, Aghdassi E, Platt I, Cullen J, Allard JP: Effect of oral iron supplementation on oxidative stress and colonic inflammation in rats with induced colitis. Aliment Pharmacol Ther 15:1989–1999, 2001

    PubMed  CAS  Google Scholar 

  11. Seril DN, Liao J, Ho KL, Warsi A, Yang CS, Yang GY: Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. Dig Dis Sci 47:1266–1278, 2002

    PubMed  CAS  Google Scholar 

  12. Grisham MB: Oxidants and free radicals in inflammatory bowel disease. Lancet 344:859–861, 1994

    Article  PubMed  CAS  Google Scholar 

  13. Morris CJ, Earl JR, Trenam CW, Blake DR: Reactive oxygen species and iron—A dangerous partnership in inflammation. Int J Biochem Cell Biol, 27:109–122, 1995

    PubMed  CAS  Google Scholar 

  14. Babbs CF: Oxygen radicals in ulcerative colitis. Free Radical Biol Med 13:169–181, 1992

    CAS  Google Scholar 

  15. Lashner BA, Silverstein MD, Hanauer SB: Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program. Dig Dis Sci 34:1536–1541, 1989

    PubMed  CAS  Google Scholar 

  16. Sugita A, Sachar DB, Bodian C, Ribeiro MB, Aufses JAH, Greenstein AJ: Colorectal cancer in ulcerative colitis. Influence of anatomical extent and age at onset on colitis-cancer interval. Gut 32:167–169, 1990

    Google Scholar 

  17. Lashner BS, Provencher KS, Bozdech, JM, Brzezinski A: Worsening risk for the development of dysplasia or cancer in patients with chronic ulcerative colitis. American Journal of Gastroenterology 90:377–380, 1995

    PubMed  CAS  Google Scholar 

  18. Fitzpatrick FA: Inflammation, carcinogenesis and cancer. International Immunopharmacology 1:1651–1667, 2001

    PubMed  CAS  Google Scholar 

  19. Seril DN, Liao J, Yang G-Y, Yang CS: Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24:353–362, 2003

    PubMed  CAS  Google Scholar 

  20. Agoff SN, Brentnall TA, Crispin DA, Taylor SL, Raaka S, Haggitt RC, Reed MW, Afonina IA, Rabinovitch PS, Stevens AC, Feng Z, Bronner MP: The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. Am J Pathol 157:737–745, 2000

    PubMed  CAS  Google Scholar 

  21. Jaiswal M. LaRusso NF, Gores GJ: Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol 281:G626–G634, 2001

    PubMed  CAS  Google Scholar 

  22. Stevens RG, Graubard BI, Micozzi MS, Neriishi K, Blumberg BS: Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int J Cancer 56:364–369, 1994

    PubMed  CAS  Google Scholar 

  23. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I: Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75:253–261, 1993

    PubMed  CAS  Google Scholar 

  24. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R: A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98:694–702, 1990

    CAS  PubMed  Google Scholar 

  25. Mahler M, Bristol IJ, Leiter EH, Workman AE, Birkenmeier EH, Elson CO, Sundberg JP: Differential susceptibility of inbred mouse strains to dextran sulfate sodium-induced colitis. Am J Physiol 274:G544–G451, 1998

    PubMed  CAS  Google Scholar 

  26. Weiss G: Iron and anemia of chronic disease. Kidney Int Suppl 69:S12–S17, 1999

    PubMed  CAS  Google Scholar 

  27. Burns DL, Pomposelli JJ: Toxicity of parenteral iron dextran therapy. Kidney Int Suppl 69:119–124, 1999

    Google Scholar 

  28. Aghdassi E, Carrier J, Cullen J, Tischler M, Allard JP: Effect of iron supplementation on oxidative stress and intestinal inflammation in rats with acute colitis. Dig Dis Sci 46:1088–1094, 2001

    PubMed  CAS  Google Scholar 

  29. Herbert V, Shaw S, Jayatilleke E, Stopler-Kasdan T: Most free-radical injury is iron-related: it is promoted by iron, hemin, holoferritin and vitamin C, and inhibited by desferoxamine and apoferritin. Stem Cells 12:289–303, 1994

    Article  PubMed  CAS  Google Scholar 

  30. Grisham MB, Granger DN: Neutrophil-mediated mucosal injury: role of reactive oxygen metabolites. Dig Dis Sci 33:6S–15S, 1988

    PubMed  CAS  Google Scholar 

  31. Sesink AL, Termont DS, Kleibeuker JH, Van der Meer R: Red meat and colon cancer: the cytotoxic and hyperproliferative effects of dietary heme. Cancer Res 59:5704–5709, 1999

    PubMed  CAS  Google Scholar 

  32. Stevens RG, Jones DY, Micozzi MS, Taylor PR: Body iron stores and the risk of cancer. N Engl J Med 319:1047–1052, 1988

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Susan L. Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854-8020, USA

    Darren N. Seril PhD, Jie Liao MD, Chung S. Yang PhD & Guang-Yu Yang MD, PhD

  2. Susan L. Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854-8020, USA

    Guang-Yu Yang MD, PhD

Authors
  1. Darren N. Seril PhD
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  2. Jie Liao MD
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  3. Chung S. Yang PhD
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  4. Guang-Yu Yang MD, PhD
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Corresponding author

Correspondence to Guang-Yu Yang MD, PhD.

Additional information

This work was supported by Research Project Grant RPG-00-034-01-CNE from the American Cancer Society and NIH Grant RO1CA104741-01A1 (G.-Y.Y.).

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Seril, D.N., Liao, J., Yang, C.S. et al. Systemic Iron Supplementation Replenishes Iron Stores Without Enhancing Colon Carcinogenesis in Murine Models of Ulcerative Colitis: Comparison with Iron-Enriched Diet. Dig Dis Sci 50, 696–707 (2005). https://doi.org/10.1007/s10620-005-2560-6

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  • DOI: https://doi.org/10.1007/s10620-005-2560-6

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