Protective Role of Aspirin, Vitamin C, and Zinc and their Effects on Zinc Status in the DMH-Induced Colon Carcinoma Model

  • Christudoss, Pamela (Department of Clinical Biochemistry, Christian Medical College) ;
  • Selvakumar, Ratnasamy (Department of Clinical Biochemistry, Christian Medical College) ;
  • Pulimood, Anna Benjamin (Department of GI, Sciences, Christian Medical College) ;
  • Fleming, Jude Joseph (Department of Clinical Biochemistry, Christian Medical College) ;
  • Mathew, George (Department of General Surgery, Christian Medical College)
  • Published : 2013.08.30


Chemoprotection refers to the use of specific natural or synthetic chemical agents to suppress or prevent the progression to cancer. The purpose of this study is to assess the protective effect of aspirin, vitamin C or zinc in a dimethyl hydrazine (DMH) colon carcinoma model in rats and to investigate the effect of these supplements on changes associated with colonic zinc status. Rats were randomly divided into three groups, group 1 (aspirin), group 2 (vitamin C) and group 3 (zinc), each being subdivided into two groups and given subcutaneous injection of DMH (30 mg/kg body wt) twice a week for 3 months and sacrificed at 4 months (A-precancer model) and 6 months (B-cancer model). Groups 1, 2, 3 were simultaneously given aspirin, vitamin C, or zinc supplement respectively from the beginning till the end of the study. It was observed that 87.5% of rats co-treated with aspirin or vitamin C showed normal colonic histology, along with a significant decrease in colonic tissue zinc at both time points. Rats co-treated with zinc showed 100% reduction in tumor incidence with no significant change in colonic tissue zinc. Plasma zinc, colonic CuZnSOD (copper-zinc superoxide dismutase) and alkaline phosphatase activity showed no significant changes in all 3 cotreated groups. These results suggest that aspirin, vitamin C or zinc given separately, exert a chemoprotective effect against chemically induced DMH colonic preneoplastic progression and colonic carcinogenesis in rats. The inhibitory effects are associated with maintaining the colonic tissue zinc levels and zinc enzymes at near normal without significant changes.


Colorectal cancer;zinc;DMH;CuZnSOD;alkaline phosphatase;vitamin C;aspirin;zinc supplement


  1. Antonio C, Isabella S, Massimo L, et al (2002). Ascorbate upregulates MLH-1 and p73: implications for the cellular response to DNA damage. Biochem J, 364, 441-7.
  2. Ashktorab H, Dawkins FW, Mohamed R, et al (2005). Apoptosis induced by aspirin and 5-fluorouracil in human colonic adenocarcinoma cells. Dig Dis Sci, 6, 1025-32.
  3. Block G (1991).Vitamin C and cancer prevention: the epidemiological evidence. Am J Clin Nutr, 53, 270-82.
  4. Bosetti C, Gallus S, Vecchia C (2009). Aspirin and cancer risk: a summary review to 2007. Cancer Res, 181, 231-51.
  5. Carpenter MP (1991). Vitamins E and C in neoplastic development. In: Laidlaw SA, Swendseid ME, Eds. Vitamins and cancer prevention. New York: Wiley-Liss, 27-37.
  6. Christos TC, Ariadni CL, Chara AS, et al (2012). Zinc and human health: an update. Arch Toxicol, 86, 521-34.
  7. Chadha VD, Garg ML, Dhawan D (2010). Influence of extraneous supplementation of zinc on trace elemental profile leading to prevention of dimethylhydrazine-induced colon carcinogenesis. Toxicol Mech Methods, 8, 493-7.
  8. Craven PA, DeRubertis FR (1992). Effect of aspirin on 1,2DMH .induced colonic carcinogenesis. Carcinogenesis, 4, 541-6.
  9. Dani V, Goel A, Vaiphei K, Dhawan DK (2007). Chemopreventive potential of zinc in experimentally induced colon carcinogenesis. Toxicol Lett, 171, 10-8 .
  10. Davis AE, Patterson F (1994). Aspirin reduces the incidence of colonic carcinoma in the dimethylhydrazine rat animal model. Aust NZ J Med, 24, 301-3.
  11. Allison M, Garland C, Chlebowski R (2006). The association between aspirin use and the incidence of colorectal cancer in women. Am J Epidemiol, 164, 567-75.
  12. Ames BN (2001). DNA damage from micronutrients deficiencies is likely to be a major cause of Cancer. Mutaton Res, 475, 7-20.
  13. Dorgan JF, Schatzkin A (1991). Antioxidant micronutrients in cancer prevention. Hematol/Oncol Clinics N Am, 5, 43-68.
  14. Dorai DT, Bachhawat BK (1977). Purification and properties of brain alkaline phosphatase. J Neurochem, 29, 503-12.
  15. Enrico F, Peter MR (2007). Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet, 379, 1591-601.
  16. Fenwick PK, Aggett PJ, Macdonald D, Huber C, Wakelin D (1990). Zinc deficiency and zinc repletion: effect on the response of rats to infection with trichinella spiralis. Am J Clin Nutr, l52, 166-72.
  17. Federico A, Iodice P, Federico P (2001). Effects of selenium and zinc supplementation on nutritional status in patients with cancer of digestive tract. Eur J Clin Nutr, 55, 293-7.
  18. Fosslien E (2000). Molecular pathology of cyclogenases -2 in neoplasia. Ann Clin Lab Sci, 30, 3-21.
  19. Fong LY, Farber JL, Magee PN (1998). Zinc replenishment reduces esophagealcell proliferation and N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumor incidence in zinc-deficient rats. Carcinogenesis, 19, 1591-6.
  20. George SS, Swaminathan S, Kanagasabapathy AS, et al (1998). Maternal zinc indices and small babies. Natl Med J India, 11, 120-1.
  21. Goh KL, Cheah PL, Md N (2007). Ethnicity and H. pylori as risk factors for gastric cancer in Malaysia: a prospective case control study. Am J Gastroenterol, 102, 40-5.
  22. Ho E, Ames BN (2002). Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFκB, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line. Proc Natl Acad Sci USA, 99, 16770-5.
  23. Ioannis AV, Anna P, Konstantinos T, et al (2010). Additive inhibition of colorectal cancer cell lines by aspirin and bortezomib. Int J Colorectal Dis, 25, 795-804.
  24. Jackson MJ (1989), Physiology of zinc: general aspect. In zinc in Human Biology, ed. CF Mills, pp 1-14. London: Springer.
  25. Jack C, Florian O, John AB, Powel HB, et al (2009). Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet & Oncol, 10, 501-7.
  26. Jayant DD, Mohini MJ, Purushottam AG (2013). ZINC: the trace element of major importance in human nutrition and health. Int J Med Sci and Public Health, 2, 1-6.
  27. Jegatheeswaran S, Mason JM, Hancock HC, Siriwardena AK (2013). The liver-first approach to the management of colorectal cancer with synchronous hepatic metastases: a systematic review. JAMA Surg, 148, 385-91.
  28. Kahnke MJ (1966). Atomic Absorption Spectrophotometry applied to determination of zinc in formalinised human tissue. At Absorption Newsl, 5, 7.
  29. Kanwar SS, Vaiphei K, Nehru B, Sanyal SN (2007). Chemopreventive effects of nonsteroidal anti-inflammatory drugs in the membrane lipid composition and fluidity parameters of the 1, 2-dimethylhydrazine-induced colon carcinogenesis in rats. Drug Chem Toxicol, 30, 293-309.
  30. Kanwar SS, Vaiphei K, Nehru B, Sanyal SN (2008). Antioxidative effects of nonsteroidal anti-inflammatory drugs during the initiation stages of experimental colon carcinogenesis in rats. J Environ Pathol Toxicol Oncol, 27, 89-100.
  31. Kim TS, Jung Y, Kim KS (2000). Molecular cloning and expression of copper and zinc containing super-oxide dismutase from Fasciola Hepatica. Infection and Immunity, 8, 3941-8.
  32. Kim JE, Kang JS, Lee WJ (2012).Vitamin C induces apoptosis in human colon cancer cell line, HCT-8 via the modulation of calcium influx in endoplasmic reticulum and the dissociation of bad from 14-3-3$\beta$. Immune Netw, 12, 189-95.
  33. Kristal AR, Stanford JL, Cohen JH, et al (1999). Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Can Epidemiol, 8, 887-92.
  34. Mahipal A, Anderson KE, Limburg J, et al (2006). Nonsteroidal anti-inflammatory drugs and subsite-specific colorectal cancer incidence in the Iowa women’s health study. Cancer Epidemiol Biomarkers Prev, 15, 1785-90.
  35. Mikirova N, Casciari J, Riordan N, et al (2013). Clinical experience with intravenous administration of ascorbic acid: achievable levels in blood for different states of inflammation and disease in cancer patients. J Transl Med, 11, 191.
  36. Michael JT, Mohan MN, Eugenia E (1992). Aspirin use and risk of fatal cancer. Am Cancer Society, 53, 322-27.
  37. Miliaras S, Miliaras D, Vrettou E, et al (2004). The effect of aspirin and high fibre diet on colorectal carcinoma: a comparative experimental study. Tech Coloproctol, 8, 59-61.
  38. Nishihara R, Lochhead P, Kuchiba A, et al (2013). Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA, 309, 2563-71.
  39. Osmak M, Kovacek I, Ljubenkov I, et al (1997). Ascorbic acid and 6-deoxy-6-chloro-ascorbic acid: potential anticancer drugs. Neoplasma, 44, 101-7.
  40. Pamela C, Selvakumar R, Anna BP, George M, et al (2012). Zinc and zinc related enzymes in precancerous and cancerous tissue in the colon of dimethyl hydrazine treated rats. Asian Pac J Cancer Prev, 13, 563-8.
  41. Patrick L (2000). Nutrients and HIV: part 2-vitamins A and E, zinc, B-vitamins, and magnesium. Alt Med Rev, 5, 39-51.
  42. Peter CE, Alison MG, Garry GD, et al (2009). Aspirin, salicylates, and cancer. Lancet, 373, 1301-9 .
  43. Poories WJ, Mansour EG, Plecha FR, et al (1976). Metabolic factors affecting zinc metabolism in the surgical patient. In: Prasad AS ed: trace elements in human health and disease. Vol 1. Zinc and Copper, New York, Academic press, 115-141.
  44. Prasad AS (1993a). Zinc and enzymes. In: Prasad AS, Ed. Biochemistry of Zinc. New York: Plenum Press, 17-53.
  45. Prasad AS (1993b). Zinc and gene expression. In: Prasad AS, Ed. Biochemistry of Zinc: New York. Plenum Press, 55-76.
  46. Prasad AS, Beck FW, Snell DC, Kucuk O (2009). Zinc in cancer prevention. Nutr Cancer, 61, 879-87.
  47. Rosenberg L, Louik C, Shapiro S, et al (1995). Expression of cyclogenase 1-and 2 in human colorectal cancer. Cancer Res, 55, 3785-9.
  48. Rosenberg L, Louik C, Shapiro S (1998). Nonsteroidal anti-inflammatory drug use and reduced risk of large bowel cancer. Cancer, 82, 2326-33.<2326::AID-CNCR5>3.0.CO;2-Q
  49. Rosner F, Garfien PC (1968). Erythrocytes and plasma zinc and magnesium levels in health and disease. J Lab Clin Med, 72, 213.
  50. Rothwell PM, Fowkes FG, Belch JF, et al (2011). Effect of daily aspirin on long-term risk of death due to cancer:analysis of individual patient data from randomised trials. Lancet, 377, 31-41.
  51. Rosa MS, Felipe L, Juan CM (2012). Radical decisions in cancer: redox control of cell growth and death. Cancers (Basel), 4, 442-73.
  52. Reddy BS, Hirota N, Katayama S (1982). Effect of dietary sodium ascorbate on 1,2-di- methylhydrazine or methylnitrosourea induced colon carcinogenesis in rats. Carcinogenesis, 3, 1097-9.
  53. Redy BS (1996). Chemoprevention of colon cancer by minor dietary constituents and their synthetic analogues. Prev Med, 25, 48-50.
  54. Riordan HD, Casciari JJ, Gonzalez MJ, et al (2005). A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. P R Health Sci J, 11, 269-76.
  55. Sathish KN, Prabhu R, Simmy T, et al (2006). Intestinal mucosal alterations in rats with carbontetrachloride-induced cirrhosis: changes in glycosylation and luminal bacteria. Hepatology, 43, 837-46.
  56. Sandler RS (1996). Aspirin and other nonsteroidal anti-inflammatory agents in the prevention of colorectal cancer. Important Adv Oncol, 1996, 123-37.
  57. Schrag D, Chung KY, Flombaum C, Saltz L (2005). Cetuximab therapy and symptomatic hypomagnesiemia. J Natl Cancer Inst, 97, 1221-4.
  58. Seung JM, In Hwa Kim (2008). Role of prostaglandins in colon cancer. Korean J Gastroenterol, 51, 274-9.
  59. Shiff SJ, Koustos MI, Giao L, et al (1996). Non steroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma :effects on cell cycle and apoptosis. Exp Cell Res, 222, 179-88.
  60. Singh S, Rana SV (2007). Amelioration of arsenic toxicity by L-Ascorbic acid in laboratory rat. J Environ Biol, 28, 377-84.
  61. Smalley W, DuBois RN (1997). Colorectal cancer and non steroidal anti-inflammatory drugs. Adv Pharmacol, 39, 1-20.
  62. Somer E (1995). Essential guide to vitamins and minerals USA.Harper Perennial, 32, 139-42.
  63. Subapriya R, Rajesh A (2008). Natural products and colon cancer: current status and future prospects. Drug Dev Res, 69, 460-71.
  64. Taccioli C, Wan SG, Liu CG, et al (2009). Zinc replenishment reverses overexpression of the proinflammatory mediator S100A8 and esophagealpreneoplasia in the rat. Gastroenterology, 136, 953-66.
  65. Wang D, DuBois RN (2006). Prostaglandins and Cancer. Gut, 55, 115-22.
  66. Williams CD (2013). Antioxidants and prevention of gastrointestinal cancers. Curr Opin Gastroenterol, 29, 195-200.
  67. Zhurkov VS, Sycheva LP, Salamatova O (1996). Selective inhibition of micronuclei in the rat/mouse colon and liver by 1,2-dimethylhydrazine . a seven tissue comparative study. Mut Res, 12, 115-20.

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