Vitamin C

• How It Works

  Vitamin C is important for maintaining general health, but vitamin C supplementation may not help lower the risk of cancer.

  Vitamin C is an essential nutrient that must be gained from sources outside the human body. It is an antioxidant used for colds and for cancer prevention because it is thought to protect cells from free radical damage. It is also important for the production of proteins and formation of collagen in the skin. Therefore, vitamin C helps promote wound healing and a deficiency can cause scurvy. In addition, scientists think that vitamin C might help reduce inflammation.

  Oral vitamin C supplements are not an effective cancer treatment. Clinical studies using high doses of injectable vitamin C do show promising results, but more studies are needed. Vitamin C may also make some chemotherapy drugs less effective. Patients should speak with their doctor before using vitamin C, especially during cancer treatment.

• Purported Uses
  • To prevent and treat the common cold and upper respiratory infections
    Vitamin C does not prevent the common cold or other upper respiratory infections, but it may slightly reduce symptoms.
  • To prevent cancer
    Some studies suggest vitamin C from food can reduce risk of certain cancers. However, most large-scale trials did not find vitamin C supplements useful in preventing cancers.
  • To treat cancer
    Clinical studies concluded oral vitamin C is not effective, probably due to limited absorption. High-doses of injectable vitamin C are currently under investigation as a cancer treatment.
  • To treat heart disease
    High dietary intake and blood levels of vitamin C have been associated with lower risk of heart disease, but a long-term study did not find benefit when taking vitamin C supplements.
  • To treat cataracts
    Vitamin C intake has no effect on development of cataracts or age-related visual loss.
  • To improve wound healing
    Intravenous vitamin C benefits severely burned patients. Other clinical trials show conflicting results for pressure sores or other wounds. Deficiencies in vitamin C can slow wound healing.
• Do Not Take If
  • You suffer from recurrent kidney stones: Increased kidney stone formation can occur and lead to kidney failure.
  • You have kidney problems or are on dialysis.
  • You have hemochromatosis: Vitamin C increases iron absorption, transport, and storage in the body.
  • You have known G6PDH (glucose-6-dehydrogenase) deficiency: Rupture of red blood cells may occur with high doses of Vitamin C.
  • You are a cancer patient undergoing radiation therapy or chemotherapy: Vitamin C may interfere with these treatments and lessen their effect.
  • You are taking bortezomib: Vitamin C may reduce the effect of this drug.
  • You are taking paracetamol: Vitamin C can increase the risk of side effects of paracetamol.
• Side Effects
  • Nausea
  • Diarrhea
  • Stomach cramps
  • Low blood sugar and low blood pressure are possible with doses greater than 1 gram.
  • Excessive use of chewable tablets may break down tooth enamel, increasing the risk of tooth erosion and decay.
• Special Point

  Laboratory experiments and animals studies suggest that cancer cells preferentially uptake vitamin C. This raises the possibility that high-dose vitamin C may be detrimental to cancer patients.

  Some practitioners recommend using vitamin C supplements to reduce the side effects of chemotherapy and radiation therapy. However, it is controversial whether antioxidants like vitamin C can also lessen the effects of these treatments, which work by creating free radicals to kill cancer cells. So what protects healthy cells may protect cancer cells as well. This question is still not fully understood and patients who are interested in taking antioxidant supplements should consult with their doctor.

• Scientific Name

  Ascorbic Acid, C6H8O6

• Clinical Summary

  Vitamin C, also known as ascorbic acid, exists as either ascorbic acid or ascorbate. It is a water-soluble vitamin that is found in many fresh fruits and vegetables, and is essential for a variety of physiologic functions including formation of collagen and catecholamines, and carnitine and peptide synthesis ⁽¹⁾. It is not synthesized in the human body, and deficiency can cause scurvy. Oral vitamin C is consumed as an antioxidant supplement for immune protection against colds and the flu, wound healing, cardiovascular health, and cancer prevention. High-dose intravenous (IV) vitamin C is being studied as a cancer treatment.

  Vitamin C has been investigated in many clinical and epidemiologic studies. Regular intake of vitamin C supplements may reduce duration and severity of the common cold. However, the effect is minimal except in people exposed to acute severe physical stress ⁽²⁾. In adults undergoing oral surgery, vitamin C reduced postoperative pain without increased side-effects ⁽⁷²⁾. It is also believed to promote cardiovascular health but findings are inconsistent. Previous studies suggest that dietary vitamin C, but not supplements, may reduce the risk of coronary heart diseases ⁽³⁾. However, two large-scale randomized trials did not find any benefits ^(4) (5). Further, supplementation with vitamins C and E increased risk of mortality and nonfatal myocardial infarction in patients with coronary artery disease ⁽⁶⁾. Data of vitamin C’s effects in reducing blood pressure are conflicting as well ^(7) (8).  Additional studies do not support prophylactic vitamin C to lower postoperative atrial fibrillation incidence among cardiac surgery patients ^(69) (70), but conflicting data show a reduction in other post-surgical side effects ⁽⁷¹⁾, and a systematic review reported reductions in the length of hospital stay, duration of mechanical ventilation, and decreased incidence of atrial fibrillation ⁽⁸⁰⁾.
  In a study of patients with sepsis and ARDS, intravenous vitamin C had no significant effect on organ dysfunction or inflammatory markers ⁽⁸⁴⁾.

  Vitamin C supplementation may reduce blood glucose and lipids in type 2 diabetes patients ⁽⁹⁾. It also decreases urinary infection rates in pregnant women ⁽¹⁰⁾; lowers incidence of organ failure and shortens ICU stay after surgery ⁽¹¹⁾; and protects against Alzheimer’s disease ^(12) (13). Vitamin C can help eradicate H. pylori infection when added to a standard medication regimen ⁽¹⁴⁾ and supplementation may potentiate treatment efficacy in some patients with thalassemia ⁽⁶⁸⁾. However, antioxidants including vitamin C do not prevent or slow the progression of age-related cataracts ⁽¹⁵⁾ or macular degeneration ⁽¹⁶⁾. Vitamin C may also reduce endurance training efficiency ⁽¹⁷⁾.

  The role of vitamin C in cancer prevention is not definitive. Conclusions of a systematic review suggest its safety ⁽⁸¹⁾ and another study showed its ability to reduce oxidative stress ⁽¹⁸⁾. Further, high plasma levels of vitamin C were associated with lower gastrointestinal cancer incidence probably due to its protective effects against dietary carcinogenic nitroso compounds ⁽¹⁹⁾. Intake of vitamins A, C, or E reduced the risk of cervical cancer ⁽²⁰⁾, but they did not prevent gastrointestinal ⁽²¹⁾, prostate ⁽²²⁾, lung cancers ⁽²³⁾ , or other cancer incidences, or affect cancer mortality ^(24) (73). In addition, vitamin C supplementation was associated with increased risk of liver cancer, although this effect was not observed with vitamin C from dietary sources ⁽²⁵⁾.

  High-dose vitamin C has been long been used as an alternative cancer treatment ⁽²⁶⁾ based on the hypothesis that the formation of new collagen resists malignant infiltration ⁽²⁷⁾. Early reports using parenteral plus oral ascorbic acid showed promising results ⁽²⁸⁾, but subsequent randomized placebo-controlled trials in advanced cancer patients using 10 g per day of oral vitamin C did not demonstrate significant benefits ^(29) (30). This lack of effect is explained by the finding of a pharmacokinetic study that ascorbic acid can only reach a limited plasma concentration through oral administration ⁽³¹⁾. A higher pharmacologic concentration, achieved only via intravenous injection, had selective cytotoxic effects on cancer cell lines ^(32) (33). Ascorbic acid is postulated to act as a carrier of hydrogen peroxide to the extracelluar fluid ⁽³²⁾ where it generates free radicals against tumor cells ⁽³³⁾. High-dose IV ascorbic acid up to 1.5 g /kg/day ⁽³⁴⁾, or used with chemotherapy ⁽⁷⁴⁾ appears to be well-tolerated. It may improve the quality of life of terminal cancer patients ⁽³⁵⁾, and reduce chemotherapy-associated toxicity ⁽⁶⁷⁾. This led to a renewed interest in studying high-dose IV vitamin C as an anticancer treatment ^(34) (36). However, it should be regarded as an investigational drug and used only in a clinical trial setting.

  There are conflicting theories against the use of vitamin C supplements during chemotherapy. Preclinical studies found that cancer cells preferentially uptake vitamin C ⁽³⁷⁾ and render some chemotherapy drugs less effective ⁽³⁸⁾. Also, a major concern surrounding the use of antioxidants such as vitamin C is that they can interfere with the actions of chemotherapy and radiation therapy that rely on the production of reactive oxygen species for their cytotoxic activities ⁽³⁹⁾. However, a clinical study showed that ascorbic acid does not reduce the therapeutic effects of paclitaxel and carboplatin ⁽⁴⁰⁾. Another study found an increase in chemotherapy-associated adverse effects with inadequate intake of vitamin C in children with acute lymphoblastic leukemia ⁽⁴¹⁾. Preliminary findings indicate that short-term vitamin C plus E supplementation during radiotherapy had a protective effect against xerostomia in patients with head and neck cancer ⁽⁷⁵⁾; and a combination of vitamins C, E, and selenium lowered radioiodine-induced oxidative stress in thyroid cancer patients ⁽⁷⁶⁾.

  Adverse effects from vitamin C are rare but there are reports of gastrointestinal upset, kidney stone formation ⁽⁴²⁾ , and hemolytic anemia in patients with G6PDH deficiency ^(43) (44). Patients with a history of oxalate kidney stones, renal insufficiency, hematochromatosis, or those undergoing chemotherapy should consult their physicians before taking vitamin C supplements.

• Food Sources

  Citrus fruits, fresh vegetables, berries, melons

• Purported Uses
  • Bronchitis
  • Cancer prevention
  • Cancer treatment
  • Cardiovascular disease
  • Cataracts
  • Common cold
  • Immunostimulation
  • Infections
  • Wound healing
• Mechanism of Action

  Vitamin C is essential for the formation and polymerization of collagen; therefore deficiency results in scurvy and poor wound healing ⁽¹⁾. Vitamin C also inhibits hyaluronidase leading to the hypothesis that it can prevent cancer metastasis by strengthening the buildup and preventing the breakdown of collagen ⁽⁴⁵⁾.

  Ascorbic acid acts as an antioxidant to protect against oxidative damage from free radicals ⁽⁴⁶⁾. It inactivates nitric oxide and improves endothelium-dependent vasodilation ⁽⁴⁷⁾, and acts via different mechanisms depending on its plasma concentration. Plasma concentrations <0.1mM are achieved through oral intake of dietary or supplemental forms. At pharmacologic plasma concentrations of 0.3 – 20mM via intravenous injection, ascorbic acid is oxidized to an ascorbate radical which acts as a prodrug for hydrogen peroxide formation within interstitial fluids ⁽³³⁾. This induces DNA damage and adenosine triphosphate (ATP) depletion, and triggers ataxia telangiectasia mutated (ATM)/adenosine monophosphate–activated protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) in cancer cells ⁽⁶⁷⁾.

  Other preclinical studies suggest that ascorbate can regulate hematopoietic stem cell function and leukemogenesis ⁽⁷⁷⁾. In leukemic cells, vitamin C compensated for Tet2 mutations to restore normal function ⁽⁷⁸⁾. In non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells, pharmacological ascorbate selectively sensitized these cells ⁽⁷⁹⁾. Ascorbate decreases colon cancer cell proliferation by downregulating specificity proteins (Sp) ⁽⁴⁸⁾. It also depletes ATP and induces autophagy and cell death in prostate cancer cells ⁽⁴⁹⁾. Preferential oxidative cytotoxic effects on cancer cells may be due to the presence of intracellular iron ⁽⁵⁰⁾, copper ⁽⁵¹⁾, an increase in p53 activity ⁽⁵²⁾, and overexpression of sodium-dependent vitamin C transporter 2 (SVCT-2) ⁽⁵³⁾. Further, high-dose vitamin C was reported to inhibit metastasis of breast cancer cells by inhibiting epithelial-mesenchymal transition ⁽⁸²⁾.

  Dehydroascorbic acid, the oxidized form of vitamin C, may have cytoprotective effects by preserving mitochondrial membrane potential ⁽³⁸⁾.

• Contraindications
  • Recurrent kidney stone formation
  • Renal impairment or on chronic hemodialysis
  • Hematochromatosis
  • Known G6PDH deficiency
• Adverse Reactions

  Common: Nausea, diarrhea and stomach cramps.

  Case reports: Oral
  Increased oxalate kidney stone formation, nephrolithiasis, acute renal failure, or renal insufficiency: In patients with history of kidney stones ^{(42) (58) (59)}.
  Hemolytic anemia: May occur at high doses in patients with G6PDH deficiency ^(43) (44).
  Severe cyanide poisoning: With concurrent use of amygdalin 3 grams + vitamin C 4800 mg per day ⁽⁶⁰⁾.
  Eroded tooth enamel or dental caries: With excessive use of chewable tablets ⁽⁶¹⁾.

  Case reports: Intravenous
  During infusion  ⁽⁷⁴⁾
  Common: Thirst and increased urinary flow.
  Isolated incidences: nausea/vomiting, rumbling or unpleasant fluttering in abdomen, chills, and/or headache.
  Post-infusion  ⁽⁷⁴⁾
  Isolated incidences: Mental haze, increased leg edema lasting for a few days.

• Herb-Drug Interactions

  Iron: Ascorbic acid increases iron absorption and modulates transport and storage in the body. Significant in patients with hematochromatosis ⁽⁶¹⁾.
  Chemotherapy drugs: Vitamin C may reduce the effectiveness of some antineoplastic agents including vincristine, doxorubicin, methotrexate, cisplatin, and imatinib ⁽³⁸⁾.
  Bortezomib: Ascorbic acid intake reduces the activity of bortezomib ⁽⁶²⁾. In a clinical trial using these agents together, the interaction is minimized by administrating bortezomib in the morning and ascorbic acid in the evening ⁽⁶³⁾.
  Glutathione: Glutathione as an antioxidant reduces the prooxidant cytotoxic effects of ascorbic acid ⁽⁶⁴⁾.
  Beta-blockers: Ascorbic acid can enhance the cardioprotective effects of beta-blockers in post-bypass patients ⁽⁶⁵⁾.
  Paracetamol: When taken simultaneously, vitamin C increased the extent of absorption of paracetamol in healthy volunteers, and may increase the risk of side effects ⁽⁸³⁾.

• Herb Lab Interactions

  Ascorbic acid supplementation may cause a false negative guaiac (occult blood) test ⁽⁶⁶⁾.

• References

  1. Sauberlich HE. Pharmacology of vitamin C. Annual review of nutrition. 1994;14:371-391.

  2. Hemila H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2013;1:CD000980.

  3. Ye Z, Song H. Antioxidant vitamins intake and the risk of coronary heart disease: meta-analysis of cohort studies. Eur J Cardiovasc Prev Rehabil. Feb 2008;15(1):26-34.

  4. Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. Nov 12 2008;300(18):2123-2133.

  5. Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med. Aug 13-27 2007;167(15):1610-1618.

  6. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. Nov 20 2002;288(19):2432-2440.

  7. Kim MK, Sasaki S, Sasazuki S, et al. Lack of long-term effect of vitamin C supplementation on blood pressure. Hypertension. Dec 2002;40(6):797-803.

  8. Mullan BA, Young IS, Fee H, et al. Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes. Hypertension. Dec 2002;40(6):804-809.

  9. Afkhami-Ardekani M, Shojaoddiny-Ardekani A. Effect of vitamin C on blood glucose, serum lipids & serum insulin in type 2 diabetes patients. Indian J Med Res. Nov 2007;126(5):471-474.

  10. Ochoa-Brust GJ, Fernandez AR, Villanueva-Ruiz GJ, et al. Daily intake of 100 mg ascorbic acid as urinary tract infection prophylactic agent during pregnancy. Acta Obstet Gynecol Scand. 2007;86(7):783-787.

  11. Nathens AB, Neff MJ, Jurkovich GJ, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. Dec 2002;236(6):814-822.

  12. Foley DJ, White LR. Dietary intake of antioxidants and risk of Alzheimer disease: food for thought. JAMA. Jun 26 2002;287(24):3261-3263.

  13. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA. Jun 26 2002;287(24):3223-3229.

  14. Zojaji H, Talaie R, Mirsattari D, et al. The efficacy of Helicobacter pylori eradication regimen with and without vitamin C supplementation. Dig Liver Dis. Sep 2009;41(9):644-647.

  15. Mathew MC, Ervin AM, Tao J, et al. Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract. Cochrane Database Syst Rev. 2012;6:CD004567.

  16. Chong EW, Wong TY, Kreis AJ, et al. Dietary antioxidants and primary prevention of age related macular degeneration: systematic review and meta-analysis. BMJ. Oct 13 2007;335(7623):755.

  17. Gomez-Cabrera MC, Domenech E, Romagnoli M, et al. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr. Jan 2008;87(1):142-149.

  18. Muralikrishnan G, Amanullah S, Basha MI, et al. Effect of vitamin C on lipidperoxidation and antioxidant status in tamoxifen-treated breast cancer patients. Chemotherapy. 2010;56(4):298-302.

  19. Loh YH, Jakszyn P, Luben RN, et al. N-Nitroso compounds and cancer incidence: the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study. Am J Clin Nutr. May 2011;93(5):1053-1061.

  20. Kim J, Kim MK, Lee JK, et al. Intakes of vitamin A, C, and E, and beta-carotene are associated with risk of cervical cancer: a case-control study in Korea. Nutr Cancer. 2010;62(2):181-189.

  21. Bjelakovic G, Nikolova D, Simonetti RG, et al. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet. Oct 2-8 2004;364(9441):1219-1228.

  22. Kirsh VA, Hayes RB, Mayne ST, et al. Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk. J Natl Cancer Inst. Feb 15 2006;98(4):245-254.

  23. Cortes-Jofre M, Rueda JR, Corsini-Munoz G, et al. Drugs for preventing lung cancer in healthy people. Cochrane Database Syst Rev. 2012;10:CD002141.

  24. Lin J, Cook NR, Albert C, et al. Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. J Natl Cancer Inst. Jan 7 2009;101(1):14-23.

  25. Zhang W, Shu XO, Li H, et al. Vitamin intake and liver cancer risk: a report from two cohort studies in China. J Natl Cancer Inst. Aug 8 2012;104(15):1173-1181.

  26. Padayatty SJ, Sun AY, Chen Q, et al. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PloS one. 2010;5(7):e11414.

  27. Cameron E, Pauling L, Leibovitz B. Ascorbic acid and cancer: a review. Cancer Res. Mar 1979;39(3):663-681.

  28. 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. Oct 1974;9(4):285-315.

  29. Creagan ET, Moertel CG, O’Fallon JR, et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. New Engl J Med. Sep 27 1979;301(13):687-690.

  30. Moertel CG, Fleming TR, Creagan ET, et al. 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. New Engl J Med. Jan 17 1985;312(3):137-141.

  31. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Int Med. Apr 6 2004;140(7):533-537.

  32. Chen Q, Espey MG, Krishna MC, et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A. Sep 20 2005;102(38):13604-13609.

  33. Chen Q, Espey MG, Sun AY, et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A. Aug 12 2008;105(32):11105-11109.

  34. Hoffer LJ, Levine M, Assouline S, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. Nov 2008;19(11):1969-1974.

  35. Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients’ health-related quality of life after high dose vitamin C administration. J Korean Med Sci. Feb 2007;22(1):7-11.

  36. Padayatty SJ, Riordan HD, Hewitt SM, et al. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ. Mar 28 2006;174(7):937-942.

  37. Agus DB, Vera JC, Golde DW. Stromal cell oxidation: a mechanism by which tumors obtain vitamin C. Cancer Res. Sep 15 1999;59(18):4555-4558.

  38. Heaney ML, Gardner JR, Karasavvas N, et al. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res. Oct 1 2008;68(19):8031-8038.

  39. Lawenda BD, Kelly KM, Ladas EJ, et al. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. Jun 4 2008;100(11):773-783.

  40. Pathak AK, Bhutani M, Guleria R, et al. Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer. J Am Coll Nutr. Feb 2005;24(1):16-21.

  41. Kennedy DD, Tucker KL, Ladas ED, et al. Low antioxidant vitamin intakes are associated with increases in adverse effects of chemotherapy in children with acute lymphoblastic leukemia. Am J Clin Nutr. Jun 2004;79(6):1029-1036.

  42. Thomas LD, Elinder CG, Tiselius HG, et al. Ascorbic acid supplements and kidney stone incidence among men: a prospective study. JAMA Int Med. Mar 11 2013;173(5):386-388.

  43. Mehta JB, Singhal SB, Mehta BC. Ascorbic-acid-induced haemolysis in G-6-PD deficiency. Lancet. Oct 13 1990;336(8720):944.

  44. Rees DC, Kelsey H, Richards JD. Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ. Mar 27 1993;306(6881):841-842.

  45. Cameron E. Vitamin C and cancer: an overview. Int J Vitam Nutr Res Suppl. 1982;23:115-127.

  46. Chen K, Suh J, Carr AC, et al. Vitamin C suppresses oxidative lipid damage in vivo, even in the presence of iron overload. Am J Physiol Endocrinol Metab. Dec 2000;279(6):E1406-1412.

  47. Taddei S, Virdis A, Ghiadoni L, et al. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation. Jun 9 1998;97(22):2222-2229.

  48. Pathi SS, Lei P, Sreevalsan S, et al. Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells. Nutr Cancer. 2011;63(7):1133-1142.

  49. Chen P, Yu J, Chalmers B, et al. Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy. Anti-Cancer Drugs. Apr 2012;23(4):437-444.

  50. Duarte TL, Almeida GM, Jones GD. Investigation of the role of extracellular H2O2 and transition metal ions in the genotoxic action of ascorbic acid in cell culture models. Toxicol Lett. Apr 5 2007;170(1):57-65.

  51. Ullah MF, Khan HY, Zubair H, et al. The antioxidant ascorbic acid mobilizes nuclear copper leading to a prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer. Cancer Chemother Pharmacol. Jan 2011;67(1):103-110.

  52. Kim J, Lee SD, Chang B, et al. Enhanced antitumor activity of vitamin C via p53 in cancer cells. Free Radic Biol Med. Oct 15 2012;53(8):1607-1615.

  53. Hong SW, Lee SH, Moon JH, et al. SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment. Oncogene. Mar 21 2013;32(12):1508-1517.

  54. Corpe CP, Tu H, Eck P, et al. Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice. J Clin Invest. Apr 2010;120(4):1069-1083.

  55. Krajcovicova-Kudlackova M, Babinska K, Valachovicova M, et al. Vitamin C protective plasma value. Bratisl Lek Listy. 2007;108(6):265-268.

  56. Robitaille L, Mamer OA, Miller WH, Jr., et al. Oxalic acid excretion after intravenous ascorbic acid administration. Metabolism. Feb 2009;58(2):263-269.

  57. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington (DC): National Academy Press; 2000.

  58. Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol. Dec 2004;15(12):3225-3232.

  59. McAllister CJ, Scowden EB, Dewberry FL, et al. Renal failure secondary to massive infusion of vitamin C. JAMA. Oct 5 1984;252(13):1684.

  60. Bromley J, Hughes BG, Leong DC, et al. Life-threatening interaction between complementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C. Ann Pharmacother. Sep 2005;39(9):1566-1569.

  61. Pronsky ZM. Food-Medication Interactions. 11th ed2000.

  62. Perrone G, Hideshima T, Ikeda H, et al. Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia. Sep 2009;23(9):1679-1686.

  63. Berenson JR, Yellin O, Woytowitz D, et al. Bortezomib, ascorbic acid and melphalan (BAM) therapy for patients with newly diagnosed multiple myeloma: an effective and well-tolerated frontline regimen. Eur J Hematol. Jun 2009;82(6):433-439.

  64. Chen P, Stone J, Sullivan G, et al. Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. Free Radic Biol Med. Aug 1 2011;51(3):681-687.

  65. Eslami M, Badkoubeh RS, Mousavi M, et al. Oral ascorbic acid in combination with beta-blockers is more effective than beta-blockers alone in the prevention of atrial fibrillation after coronary artery bypass grafting. Tex Heart Inst J. 2007;34(3):268-274.

  66. Jaffe RM, Kasten B, Young DS, et al. False-negative stool occult blood tests caused by ingestion of ascorbic acid (vitamin C). Ann Int Med. Dec 1975;83(6):824-826.

  67. Ma Y, Chapman J, Levine M. High-Dose Parenteral Ascorbate Enhanced Chemosensitivity of Ovarian Cancer and Reduced Toxicity of Chemotherapy. Sci Transl Med. 5 February 2014. Vol. 6, Issue 222, p. 222ra18. DOI: 10.1126/scitranslmed.3007154.

  68. Elalfy MS, Saber MM, Adly AA, et al. Role of vitamin C as an adjuvant therapy to different iron chelators in young beta-thalassemia major patients: efficacy and safety in relation to tissue iron overload. Eur J Haematol. Mar 2016;96(3):318-326.

  69. Antonic M, Lipovec R, Gregorcic F, et al. Perioperative ascorbic acid supplementation does not reduce the incidence of postoperative atrial fibrillation in on-pump coronary artery bypass graft patients. J Cardiol. Jan 2017;69(1):98-102.

  70. Colby JA, Chen WT, Baker WL, et al. Effect of ascorbic acid on inflammatory markers after cardiothoracic surgery. Am J Health Syst Pharm. Sep 01 2011;68(17):1632-1639.

  71. Safaei N, Babaei H, Azarfarin R, et al. Comparative effect of grape seed extract (Vitis vinifera) and ascorbic acid in oxidative stress induced by on-pump coronary artery bypass surgery. Ann Card Anaesth. Jan-Mar 2017;20(1):45-51.

  72. Ayatollahi V, Dehghanpour Farashah S, Behdad S, et al. Effect of intravenous vitamin C on postoperative pain in uvulopalatopharyngoplasty with tonsillectomy. Clin Otolaryngol. Feb 2017;42(1):139-143.

  73. Wang L, Sesso HD, Glynn RJ, et al. Vitamin E and C supplementation and risk of cancer in men: posttrial follow-up in the Physicians’ Health Study II randomized trial. Am J Clin Nutr. Sep 2014;100(3):915-923.

  74. Hoffer LJ, Robitaille L, Zakarian R, et al. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PLoS One. 2015;10(4):e0120228.

  75. Chung MK, Kim do H, Ahn YC, et al. Randomized Trial of Vitamin C/E Complex for Prevention of Radiation-Induced Xerostomia in Patients with Head and Neck Cancer. Otolaryngol Head Neck Surg. Sep 2016;155(3):423-430.

  76. Rosario PW, Batista KC, Calsolari MR. Radioiodine-induced oxidative stress in patients with differentiated thyroid carcinoma and effect of supplementation with vitamins C and E and selenium (antioxidants). Arch Endocrinol Metab. Aug 2016;60(4):328-332.

  77. Agathocleous M, Meacham CE, Burgess RJ, et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. Aug 21 2017.

  78. Cimmino L, Dolgalev I, Wang Y, et al. Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell. Aug 16 2017.

  79. Schoenfeld JD, Sibenaller ZA, Mapuskar KA, et al. O2- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell. Apr 10 2017;31(4):487-500.e488.

  80. Hill A, Clasen KC, Wendt S, et al. Effects of Vitamin C on Organ Function in Cardiac Surgery Patients: A Systematic Review and Meta-Analysis. Nutrients. 2019 Sep 4;11(9). pii: E2103.

  81. van Gorkom GNY, Lookermans EL, Van Elssen CHMJ, Bos GMJ. The Effect of Vitamin C (Ascorbic Acid) in the Treatment of Patients with Cancer: A Systematic Review. Nutrients. 2019 Apr 28;11(5). pii: E977.

  82. Zeng LH, Wang QM, Feng LY, et al. High-dose vitamin C suppresses the invasion and metastasis of breast cancer cells via inhibiting epithelial-mesenchymal transition. Onco Targets Ther. 2019 Sep 10;12:7405-7413.

  83. Jaccob AA, Ahmed ZH, Aljasani BM. Vitamin C, omega-3 and paracetamol pharmacokinetic interactions using saliva specimens as determiners. J Basic Clin Physiol Pharmacol. 2019 Aug 6;30(5).

  84. Fowler AA 3rd, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019 Oct 1;322(13):1261-1270.