Regular Article

BJC Open article

British Journal of Cancer (2001) 84, 1544–1550. doi:10.1054/bjoc.2001.1814 www.bjcancer.com
Published online 29 May 2001

Cytotoxicity of ascorbate, lipoic acid, and other antioxidants in hollow fibre in vitro tumours

J J Casciari1, N H Riordan1,*, T L Schmidt1, X L Meng1, J A Jackson2 and H D Riordan1

  1. 1Bio-Communications Research Institute, Center for the Improvement of Human Functioning International, 3100 North Hillside Avenue, Wichita, KS, 67219
  2. 2Department of Medical Technology, Wichita State University, Wichita, KS, 67260

*Aidan Incorporated, 621 South 48th Street, Suite 111, Tempe, AZ 85281

Received 11 August 2000; Revised 23 January 2001; Accepted 9 February 2001

Top

Abstract

Vitamin C (ascorbate) is toxic to tumour cells, and has been suggested as an adjuvant cancer treatment. Our goal was to determine if ascorbate, in combination with other antioxidants, could kill cells in the SW620 hollow fibre in vitro solid tumour model at clinically achievable concentrations. Ascorbate anti-cancer efficacy, alone or in combination with lipoic acid, vitamin K3, phenyl ascorbate, or doxorubicin, was assessed using annexin V staining and standard survival assays. 2-day treatments with 10 mM ascorbate increased the percentage of apoptotic cells in SW620 hollow fibre tumours. Lipoic acid synergistically enhanced ascorbate cytotoxicity, reducing the 2-day LC50 in hollow fibre tumours from 34 mM to 4 mM. Lipoic acid, unlike ascorbate, was equally effective against proliferating and non-proliferating cells. Ascorbate levels in human blood plasma were measured during and after intravenous ascorbate infusions. Infusions of 60 g produced peak plasma concentrations exceeding 20 mM with an area under the curve (24 h) of 76 mM h. Thus, tumoricidal concentrations may be achievable in vivo. Ascorbate efficacy was enhanced in an additive fashion by phenyl ascorbate or vitamin K3. The effect of ascorbate on doxorubicin efficacy was concentration dependent; low doses were protective while high doses increased cell killing. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords:

ascorbic acid (vitamin C); thioctic acid (lipoic acid); vitamin K; tumour cells, cultured; dose–response relationship, drug

Top

References

  1. Agus DB, Vera JC and Golde DW (1999) Stromal cell oxidation: a mechanism by which tumors obtain vitamin C. Cancer Res 59: 4555–4558
  2. Benade L, Howard T and Burk D (1969) Synergistic killing of Ehrlich ascites carcinoma cells by ascorbate and 3-amino-1,2,4,-triazole. Oncology 23: 33–43 | PubMed | ISI | ChemPort |
  3. Bram S, Froussard P, Guichard M, Jasmin C, Augery Y, Sinoussi-Barre F and Wray W (1980) Vitamin C preferential toxicity for malignant melanoma cells. Nature 284: 629–631 | Article | PubMed | ISI | ChemPort |
  4. Cameron E and Campbell A (1974) The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact 9: 285–315
  5. Cameron E and Pauling L (1976) Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA 73: 3685–3689
  6. Cameron E, Pauling L and Leibovitz B (1979) Ascorbic acid and cancer: a review. Cancer Res 39: 663–681 | PubMed | ISI | ChemPort |
  7. Casciari JJ, Hollingshead MG, Alley MC, Mayo JG, Malspeis L, Miyauchi S, Grever MR and Weinstein JN (1994) Growth and chemotherapeutic response of cells in a hollow fiber in vitro solid tumor model. J Natl Cancer Inst 86: 1846–1852
  8. Collins JM (1996) Pharmacokinetics and clinical monitoring. In: Cancer Chemotherapy and Biotherapy, Chabner BA, Longo DL (eds) pp 17–30. Lippincott-Raven Publishers: Philadelphia
  9. Creagan ET, Moertel CG, O'Fallon JR, Schutt AJ, O'Connell MJ, Rubin J and Frytak S (1979) 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 | PubMed | ISI | ChemPort |
  10. Fujita K, Shinpo K, Yamada K, Sato T, Niimi H, Shamoto M, Nagatsu T, Takeuchi T and Umezawa H (1982) Reduction of adriamycin toxicity by ascorbate in mice and guinea pigs. Cancer Res 42: 309–316
  11. Goldschmidt MC (1991) Reduced bactericidal activity in neutrophils from scorbutic animals and the effect of ascorbic acid on these target bacteria in vivo and in vitro. Am J Clin Nutr 54: 1214S–1220S
  12. Henry RJ, Cannon DC and Winkleman JW (1974) Determination of Ascorbic Acid. In: Clinical Chemistry: Principles and Techniques pp 1393–1398. Harper & Row: New York
  13. Henson DE, Block G and Levine M (1991) Ascorbic acid: biologic functions and relation to cancer. J Natl Cancer Inst 83: 547–550
  14. Hornig D (1975) Distribution of ascorbic acid, metabolites and analogues in man and animals. Ann N Y Acad Sci 258: 103–118
  15. Jackson JA, Riordan HD, Hunninghauke RE and Riordan N (1995) High dose intravenous vitamin C and long time survival of a patient with cancer of the head of the pancreas. J Ortho Med 10: 87–88
  16. Jonas SK, Riley PA and Willson RL (1989) Hydrogen peroxide cytotoxicity: low-temperature enhancement by ascorbate or reduced lipoate. Biochem J 265: 651–655
  17. Koch CJ and Biaglow JE (1978) Toxicity, radiation sensitivity modification, and metabolic effects of dehydroascorbate and ascorbate in mammalian cells. J Cell Physiol 94: 299–306 | PubMed | ISI | ChemPort |
  18. Kurbacher CM, Wagner U, Kolster B, Andreotti PE, Krebs D and Bruckner HW (1996) Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro. Cancer Lett 103: 183–189
  19. Langemann H, Torhorst J, Kabiersch A, Krenger W and Honegger CC (1989) Quantititve determination of water and lipid soluble antioxidants in neoplastic and non-neoplastic human breast tissue. Int. J. Cancer 43: 1169–1173
  20. Leung PY, Miyashita K, Young M and Tsao CS (1993) Cytotoxic effect of ascorbate and its derivatives on cultured malignant and nonmalignant cell lines. Anticancer Res 13: 475–480
  21. Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ and Ames MM (1985) 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 | PubMed | ISI | ChemPort |
  22. Murata A, Morishige F and Yamaguchi H (1982) Prolongation of survival times of terminal cancer patients by administration of large doses of ascorbate. Int J Vitam Nutr Res Suppl 23: 103–113
  23. Noto V, Taper HS, Jiang YH, Janssens J, Bonte J and De Loecker W (1989) Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. I. Synergism of combined vitamin C and K3 action. Cancer 63: 901–906
  24. Okunieff P and Suit HD (1987) Toxicity, radiation sensitivity modification, and combined drug effects of ascorbic acid with misonidazole in vivo on FSaII murine fibrosarcomas. J Natl Cancer Inst 79: 377–381
  25. Ou P, Tritschler HJ and Wolff SP (1995) Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant?. Biochemical Pharmacology 50: 123–126
  26. Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH and Belfield PW (1991) The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial. Age Ageing 20: 169–174
  27. Raloff J (2000) Antioxidants may help cancers thrive. Science News 157: 5
  28. Riordan HD, Jackson JA, Riordan NH and Schultz M (1998) High-dose intravenous vitamin C in the treatment of a patient with renal cell carcinoma of the kidney. J Ortho Med 13: 72–73
  29. Riordan HR, Jackson JA and Schultz M (1990) Case study: high-dose intravenous vitamin C in the treatment of a patient with adenocarcinoma of the kidney. J Ortho Med 5: 5–7
  30. Riordan NH, Riordan HD, Meng X, Li Y and Jackson JA (1995) Intravenous ascorbate as a tumor cytotoxic chemotherapeutic agent. Med Hypotheses 44: 207–213
  31. Taper HS, Keyeux A and Roberfroid M (1996) Potentiation of radiotherapy by nontoxic pretreatment with combined vitamins C and K3 in mice bearing solid transplantable tumor. Anticancer Res 16: 499–503
  32. Tsao CS, Dunham WB and Leung PY (1988) In vivo antineoplastic activity of ascorbic acid for human mammary tumor. In Vivo 2: 147–150
  33. Varga JM and Airoldi L (1983) Inhibition of transplantable melanoma tumor development in mice by prophylactic administration of Ca-ascorbate. Life Sci 32: 1559–1564
BJC Open article

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.
To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/