DOI QR코드

DOI QR Code

The Prospects of Vitamin C in Cancer Therapy

  • Lee, Wang-Jae (Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine)
  • Received : 2009.09.03
  • Accepted : 2009.09.08
  • Published : 2009.10.31

Abstract

Ascorbate (vitamin C) is a cofactor for a number of metabolic enzymes and is an indisputable essential vitamin C for humans. However, the potential of ascorbate as an anticancer agent has been a topic of controversy. A number of previous reports have addressed both positive aspects and limitations of ascorbate in cancer therapy. In this review, we briefly summarize the potential antitumor effects of ascorbate and its prospects for clinical use.

Keywords

References

  1. Cameron E, Pauling L, Leibovitz B: Ascorbic acid and cancer: a review. Cancer Res 39;663-681, 1979
  2. Golde DW: Vitamin C in cancer. Integr Cancer Ther 2; 158-159, 2003 https://doi.org/10.1177/1534735403002002009
  3. Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 75;4538-4542, 1978 https://doi.org/10.1073/pnas.75.9.4538
  4. Padayatty SJ, Levine M: Reevaluation of ascorbate in cancer treatment: emerqing evidence, open minds and serendipity. J Am Coll Nutr 19;423-425, 2000 https://doi.org/10.1080/07315724.2000.10718941
  5. Creagan ET, Moertel CG, O'Fallon JR, Schutt AJ, O'Connell MJ, Rubin J, Frytak S: Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med 301; 687-690, 1979 https://doi.org/10.1056/NEJM197909273011303
  6. Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, Ames MM: High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med 312;137-141, 1985 https://doi.org/10.1056/NEJM198501173120301
  7. Wittes RE: Vitamin C and cancer. N Engl J Med 312;178-179, 1985 https://doi.org/10.1056/NEJM198501173120310
  8. McCormick WJ: Cancer: the preconditioning factor in pathogenesis; a new etiologic approach. Arch Pediatr 71;313-322, 1954
  9. McCormick WJ: Cancer: a collagen disease, secondary to a nutritional deficiency. Arch Pediatr 76;166-171, 1959
  10. Cameron E, Rotman D: Ascorbic acid, cell proliferation, and cancer. Lancet 1;542, 1972
  11. Cameron E, Pauling L: Ascorbic acid and the glycosaminoglycans. An orthomolecular approach to cancer and other diseases. Oncology 27;181-192, 1973 https://doi.org/10.1159/000224733
  12. Cameron E, Campbell A: The orthomolecular treatment of cancer, II: clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact 9; 285-315, 1974 https://doi.org/10.1016/0009-2797(74)90019-2
  13. Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 73;3685-3689, 1976 https://doi.org/10.1073/pnas.73.10.3685
  14. Head KA: Ascobic acid in the prevention and treatment of cancer. Altern Med Rev 3;174-186, 1998
  15. Cameron E, Campbell A: Innovation vs. quality control: an 'unpublishable' clinical trial of supplemental ascorbate in incurable cancer. Med Hypotheses 36;185-189, 1991 https://doi.org/10.1016/0306-9877(91)90127-K
  16. Graumlich JF, Ludden TM, Conry-Cantilena C, Cantilena LR Jr, Wang Y, Levine M: Pharmacokinetics model of ascorbic acid in healthy male volunteers during depletion and repletion. Pharm Res 14;1133-1139, 1997 https://doi.org/10.1023/A:1012186203165
  17. Satoshi O, Yumiko O, Nobutaka S, Gen-Ichiro S, Masaki I: High-dose vitamin C (Ascorbic acid) therapy in the treatment of patient with advanced cancer. Anticancer Res 29;809-816, 2009
  18. Keith I, Block MD, Mark N, Mead MS: Vitamin C in alternative cancer treatment: Historical background. Integrative Cancer Therapies 2;147-154, 2003 https://doi.org/10.1177/1534735403002002007
  19. Gonzalez MJ, Miranda-Massari JR, Mora EM, Guzman A, Riordan NH, Riordan HD, Casciari JJ, Jackson JA, Raman-Franco A: Orthomolecular oncology review: ascorbic acid and cancer 25 years later. Interg cancer therapies 4;32-44, 2005 https://doi.org/10.1177/1534735404273861
  20. Levine M: New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med 314;892-902, 1986 https://doi.org/10.1056/NEJM198604033141407
  21. Block G: Vitamin C and cancer prevention: the epidemiologic evidence. Am J Clin Nutr 53;s270-282, 1991 https://doi.org/10.1093/ajcn/53.1.270S
  22. Rebouche CJ: Ascorbic acid and carnitine biosynthesis. Am J Clin Nutr 54;s1147-1152, 1991 https://doi.org/10.1093/ajcn/54.6.1147s
  23. Englard S, Seifter S: The biochemical functions of ascorbic acid. Annu Rev Nutr 6;365-406, 1986 https://doi.org/10.1146/annurev.nu.06.070186.002053
  24. Sies H, Stahl W, Sundquist AR: Antioxidant functions of vitamins. Vitamins E and C, beta-carotene and other carotenioids. Ann N Y Acad Sci 669;7-20, 1992 https://doi.org/10.1111/j.1749-6632.1992.tb17085.x
  25. Niki E: Action of ascorbic acid as a scavenger of active and stable oxygen radicals. Am J Clin Nutr 54;1119-1124, 1991 https://doi.org/10.1093/ajcn/54.6.1119s
  26. Frei B, England L, Ames B: Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A 86;6377-6381, 1989 https://doi.org/10.1073/pnas.86.16.6377
  27. Ramp WK, Thorton PA: The effects of ascorbic acid on the glycolytic and respiratory metabolism of embryonic chick tibias. Calcif Tissue Res 2;77-82, 1968
  28. Mikino Y, Sakagami H, Takeda M: Induction of cell death by ascorbic acid derivatives in human renal carcinoma and glioblastoma cell lines. Anticancer Res 19;3125-3132, 1999
  29. Poydock ME, Reikert D, Rice J, Aleandri L: Inhibiting effect of dehydroascorbic acid on cell division in ascites tumors in mice. Exp Cell Biol 50;34-38, 1982
  30. Tomita Y, Eto M, Lio M: Antitumor potency of 3-methyl-3,4-dihydroxytetrone. Sci Bull Fac Agr Kyushu Univ 28;131-137, 1974
  31. Gonzalez MJ, Mora E, Riordan NH, Riordan HD, Mojica P: Rethinking vitamin C and cancer: an uptake on nutritional oncology. Cancer Prev Int 3;215-224, 1998 https://doi.org/10.3727/108399898791838333
  32. Jampel HD: Ascorbic acid is cytotoxic to dividing human Tenon's capsule fibroblasts. A possible contributing factor in glaucoma filtration surgery success. Arch Ophthalmol 108;1323-1325, 1990 https://doi.org/10.1001/archopht.1990.01070110139038
  33. Tsao CS, Dunhan WB, Leung PY: In vivo antineoplastic activity of ascorbic acid for human mammary tumor. In vivo 2;147-150, 1988
  34. Tsao CS, Dunhan WB, Leung PY: Effect of ascorbic acid and its derivatives on the growth of human mammary tumor xenografts in mice. Cancer J 5;53-59, 1989
  35. Bram S, Froussard P, Guichard M, Jasmin C, Augery Y, Sinoussi-Barre F, Wray W: Vitamin C preferential toxicity for malignant melanoma cells. Nature 284;629-631, 1980 https://doi.org/10.1038/284629a0
  36. Sies H, Stahl W: Vitamin E and C, beta-carotene, and other carotenoids as antioxidants. Am J Clin Nutr 62;1315-1321, 1995 https://doi.org/10.1093/ajcn/62.6.1315S
  37. Hemila H: Vitamin C and the common cold. Br J Nutr 67;3-16, 1992 https://doi.org/10.1079/BJN19920004
  38. Jeng KC, Yang CS, Siu WY, Tsai YS, Liao WJ, Kuo JS: Supplementation with vitamin C and E enhances cytokine production by peripheral blood mononuclear cells in heathly adults. Am J Clin Nutr 64;960-965, 1996 https://doi.org/10.1093/ajcn/64.6.960
  39. Cho D, Hahm E, Kang JS, Kim YI, Yang YH, Park JH, Kim D, Kim S, Kim YS, Hur D, Park H, Pang S, Hwang YI, Lee WJ: Vitamin C downregulates interleukin-18 production by increasing reactive oxygen intermediate and mitogen-activated protein kinase signaling in B16F10 murine melanoma cells. Melano Res 13;549-554, 2003 https://doi.org/10.1097/00008390-200312000-00002
  40. Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K, et al: Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378;88-91, 1995 https://doi.org/10.1038/378088a0
  41. Park HU, Byun DG, Kim TG, Kim YI, Kang JS, Hahm ES, Lee WJ: Enhanced IL-18 expression in common skin tumors. Immunol Lett 79;215-219, 2001 https://doi.org/10.1016/S0165-2478(01)00278-4
  42. Kim KE, Song H, Kim TS, Yoon D, Kim CW, Bang SI, Hur DY, Park H, Cho DH: Interleukin-18 is a critical factor for vascular endothelial growth factor-enhanced migration in human gastric cancer cell lines. Oncogene 26;1468-1476, 2007 https://doi.org/10.1038/sj.onc.1209926
  43. Park S, Yoon SY, Kim KE, Lee HR, Hur DY, Song H, Kim D, Bang SI, Cho DH: Interleukin-18 induces transferrin expression in breast cancer cell line MCF-7. Cancer Lett 2009 Jun 15 https://doi.org/10.1016/j.canlet.2009.05.025
  44. Park S, Cheon S, Cho D: The dual effects of interleukin-18 in tumor progression. Cell & Mol Immunol 4; 329-335, 2007
  45. Vera JC, Rivas CI, Fischbarg J, Golde DW: Mammalian facilitative hexose transports mediate the transport of dehydroascorbic acid. Nature 364;79-82, 1993 https://doi.org/10.1038/364079a0
  46. Vera JC, Rivas CI, Zhang RH, Farber CM, Golde DW: Human HL-60 myeloid leukemia cells transport dehydroascorbic acid via the glucose transporters and accumulate reduced ascorbic acid. Blood 84;1628-1634
  47. Guaiquil VH, Farber CM, Golde DW, Vera JC: Efficient transport and accumulation of vitamin C in HL-60 cells depleted of glutathione. J Biol Chem 272;9915-9921, 1997 https://doi.org/10.1074/jbc.272.15.9915
  48. Guaiquil VH, Vera JC, Golde DW: Mechanism of vitamin C inhibition of cell death induced by oxidative stress in glutathione-depleted HL-60 cells. J Biol Chem 276;40955-40961, 2001 https://doi.org/10.1074/jbc.M106878200
  49. Galleano M, Aimo L, Puntarulo S: Ascorbyl radical/ascorbate ratio in plasma from iron overloaded rats as oxidative stress indicator. Toxical Lett 133;193-201, 2002 https://doi.org/10.1016/S0378-4274(02)00196-0
  50. Heaney ML, Gardner JR, Karasavvas N, Golde DW, Scheinberg DA, Smith EA, O'Connor OA: Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res 68;8031-8038, 2008 https://doi.org/10.1158/0008-5472.CAN-08-1490
  51. Lee SH, Oe T, Blair IA: Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science 292;2083-2086, 2001 https://doi.org/10.1126/science.1059501
  52. Lee KW, Lee HJ, Surh YJ, Lee CY: Vitamin C and cancer chemoprevention: reappraisal. Am J Clin Nutr 78;1074-1078, 2003 https://doi.org/10.1093/ajcn/78.6.1074
  53. Levine M, Wang Y, Padayatty SJ, Morrow J: A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci U S A 98;9842-9846, 2001 https://doi.org/10.1073/pnas.171318198
  54. Hahm E, Jin DH, Kang JS, Kim YI, Hong SW, Lee SK, Kim HN, Jung da J, Kim JE, Shin DH, Hwang YI, Kim YS, Hur DY, Yang Y, Cho D, Lee MS, Lee WJ: The molecular mechanisms of vitamin C on cell cycle regulation in B16F10 murine melanoma. J Cell Biochem 102;1002-1010, 2007 https://doi.org/10.1002/jcb.21336
  55. Kang JS, Cho D, Kim YI, Hahm E, Yang Y, Kim D, Hur D, Park H, Bang S, Hwang YI, Lee WJ: L-ascorbic acid (vitamin C) induces the apoptotic of B16 murine melanoma cells via a caspase-8-independent pathway. Cancer Immunol Immunother 52;693-698, 2003 https://doi.org/10.1007/s00262-003-0407-6
  56. Kim JE, Jin DH, Lee SD, Hong SW, Shin JS, Lee SK, Jun DJ, Kang JS, Lee WJ: Vitamin C inhibits p53-induced replicative senescence through suppression of ROS production and p38 MAPK activity. Int J Mol Med 22;651-655, 2008
  57. Lee SK, Kang JS, Jung da J, Hur DY, Kim JE, Hahm E, Bae S, Kim HW, Kim D, Cho BJ, Cho D, Shin DH, Hwang YI, Lee WJ: Vitamin C suppresses proliferation of the human melanoma cell SK-MEL-2 through the inhibition of cyclo-oxygenase (COX-2) expression and the modulation of insulin-like growth factor (IGF-II) production. J Cell Physiol 216;180-188, 2008 https://doi.org/10.1002/jcp.21391
  58. Ashino H, Shimamura M, NaKajima H, Dombou M, Kawanaka S, Oikawa T, Iwaguchi T, Kawashima S: Novel function of ascorbic acid as an angiostatic factor. Angiogenesis 6;259-269, 2003 https://doi.org/10.1023/B:AGEN.0000029390.09354.f8
  59. Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, Khosh DB, Drisko J, Levine M: Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A 105;11105-11109, 2008 https://doi.org/10.1073/pnas.0804226105
  60. Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E, Choyke PL, Pooput C, Kirk KL, Buettner GR, Levine M: Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid In vivo. Proc Natl Acad Sci U S A 104;8749-8754, 2007 https://doi.org/10.1073/pnas.0702854104
  61. White JD: Complementary and alternative medicine research: a National Cancer institue perspective. Semin Oncol 29;546-551, 2002 https://doi.org/10.1053/sonc.2002.50003
  62. Nahin RL: Use of the best case series to evaluate complementary and alternative therapies for cancer: a systematic review. Semin Oncol 29;552-562, 2002 https://doi.org/10.1053/sonc.2002.50004
  63. Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M: Intravenously administered vitamin C as cancer therapy: three cases. CMAJ 174;937-942, 2006 https://doi.org/10.1503/cmaj.050346

Cited by

  1. Vitamin K3 and vitamin C alone or in combination induced apoptosis in leukemia cells by a similar oxidative stress signalling mechanism vol.11, pp.None, 2009, https://doi.org/10.1186/1475-2867-11-19
  2. Impacto da suplementação de vitamina C sobre níveis de peroxidação lipídica e glutationa reduzida em tecido hepático de camundongos com imunossupress vol.29, pp.4, 2016, https://doi.org/10.1590/1678-98652016000400012
  3. Combined treatment with vitamin C and methotrexate inhibits triple-negative breast cancer cell growth by increasing H2O2 accumulation and activating caspase-3 and p38 pathways vol.37, pp.4, 2017, https://doi.org/10.3892/or.2017.5439
  4. Vitamin A Enhances Macrophages Activity Against B16-F10 Malignant Melanocytes: A New Player for Cancer Immunotherapy? vol.55, pp.9, 2009, https://doi.org/10.3390/medicina55090604
  5. Combination Therapy with Vitamin C Could Eradicate Cancer Stem Cells vol.10, pp.1, 2020, https://doi.org/10.3390/biom10010079
  6. The benefits of ascorbate to protect healthy cells in the prevention and treatment of oncological diseases vol.18, pp.1, 2020, https://doi.org/10.32725/jab.2020.003
  7. Antioxidant vitamins promote anticancer effects on low‐concentration methotrexate‐treated glioblastoma cells via enhancing the caspase‐3 death pathway vol.9, pp.6, 2009, https://doi.org/10.1002/fsn3.2298
  8. Understanding the Therapeutic Potential of Ascorbic Acid in the Battle to Overcome Cancer vol.11, pp.8, 2009, https://doi.org/10.3390/biom11081130