Vitamin C Therapy: An Invaluable, Safe, Effective Therapy

by | Jun 19, 2023 | Articles

Vitamin C in Medicine: An Invaluable, Safe, Effective Therapy
This is an article designed for educational purposes only, and is not meant as medical advice.
Vitamin C (Ascorbic acid) has many beneficial functions in the human body. It is important to note that humans are one of the few species not capable of manufacturing vitamin C internally, and thus, are reliant on food sources of vitamin C for survival. This can lead to body levels inadequate for cellular protection. The following is a list of the main functions Vitamin C has in the human body:
  • This nutrient plays a major role in the manufacture and defense of our connective tissue, the elaborate matrix that holds the body together. It is a primary ingredient in collagen, a glue-like substance that binds cells together to form tissues. It strengthens and improves the health of joint tissue, tendons, ligaments, skin, hair, teeth, gums, blood vessels, intestinal lining, and all the sensory and glandular organs.
  • Vitamin C stimulates the immune system to fight off foreign invaders and tumor cells.
  • Vitamin C is vital for heart and circulatory health by facilitating fat metabolism, protecting vessels from free radical damage, and strengthening blood vessel walls.
  • Vitamin C maintains healthy bones, teeth, gums, tissues. It aids in wound healing.
  • Vitamin C combats inflammation and pain. It behaves like a “natural aspirin”.
  • At high doses only reached by intravenous injection, Vitamin C confers benefits for cancer patients. It has been shown to increase survival times in cancer patients, decrease the amount of radiation required, enhance the effect of chemotherapy, protect from the damage of radiation and chemotherapy, inhibit the growth of some cancers, and reverse some abnormal cell lines back to normal. It is known to enhance both quality and quantity of life. Up to 75 grams can be infused intravenously over a period of 2-3hours, 2-3 times weekly. (Intravenous Vitamin C is not a cancer cure).
  • Vitamin C is a potent neutralizer and detoxifier of toxins such as pesticides, alcohol, nicotine, aluminum, cadmium, nickel, lead, fluoride, PCB’s, etc. It not only neutralizes and removes these toxins from the body, but it protects our healthy cells from being damaged by these toxins.
  • Vitamin C is a potent anti-viral, anti-bacterial, and anti-parasitic agent. Oral vitamin C helps protect the body from developing infections, and high-dose intravenous vitamin C is an effective method of destroying and removing pathogenic microbes. Intravenous vitamin C has cured viral infections which can be debilitating and even life threatening such as swine flu, measles, mumps, viral encephalitis, chicken pox, shingles, herpes, viral pneumonia, colds, and flus. (Intravenous Vitamin C should be used adjunctively with conventional anti-microbial medication to augment and improve outcomes).
Vitamin C therapy both orally and intravenously has been used successfully by trained doctors for many years and is backed by volumes of research. It has proven itself to be safe and effective for several toxic, infective, and cancerous conditions. Talk to a trained Naturopathic Doctor to discover how this simple, inexpensive nutrient can benefit your health. This is not to say that this therapy should replace conventional medical advice. As always, collaborative therapy amongst all health care providers is the best overall approach.
To protect your health, it is important to supplement with pure ascorbic acid (vitamin C) buffered with sodium in the form or sodium-ascorbate powder in gram doses daily. Everyone has their own individual dose which is the “bowel tolerance” dose. Take the vitamin C in divided doses throughout the day, at least 3 times daily. Start with 500mg 3 times daily and if tolerated, increase to 1000mg 3 times daily. Continue increasing until regular bowel movements are achieved (at least once daily, soft but not diarrhea). If illness occurs, increase the dose incrementally because when sick, the body will use up more vitamin C to fight the illness. You should notice that your bowel tolerance dose increases when you are sick. Sodium ascorbate powder mixed in water or other liquids is the most economical and easy method of achieving optimal dosing. Adding liposomal vitamin C may be necessary in severe illness. Liposomal vitamin C is a fat soluble, very absorbable form of vitamin C that will not affect the bowel. Take a dose of 5 grams 3 times daily. This significantly increases intracellular levels of ascorbic acid which enhances the anti-microbial and anti-toxin effect. With severe infections, cancer, or inflammation, consider intravenous Vitamin C which will greatly increase the intracellular levels of this nutrient and act as a precursor to hydrogen peroxide which cancer cells and pathogens have little defense against. Normal cells contain the enzyme catalase which neutralizes the hydrogen peroxide and are therefore, unharmed by it. Pathogens and cancer cells accumulate excess iron as well as being deficient in catalase, making them particularly vulnerable to the effects of high dose vitamin C.
Vitamin C has an extremely good safety profile, and there is no toxicity associated at any dose. Electrolyte and blood glucose levels can be affected by intravenous infusion, therefore, these are monitored and adjusted for. Starting at lower doses and going slow helps to mitigate any issues. A rare enzyme deficiency (G-6PD) can lead to hemolysis, or red blood cell membrane breakage, with high dose IV-Vitamin C. This can be tested for prior to treatment. Also, end stage kidney disease is a contraindication for IV-Vitamin C and fluid overload conditions such as congestive heart failure are conditionally contraindicated. A doctor trained and experienced in IV therapy will ensure the safe use of this therapy.
For comprehensive scientific reviews and therapeutic uses of Vitamin C watch documentaries and lectures by the experts in the field on You tube or other podcast platforms such as: Dr. Thomas Levy: “Vitamin C and Antioxidant Therapy” (or read his book, “Vitamin C, Infectious Diseases, and Toxins”), and Dr. Suzanne Humphries, “Lecture on Vitamin C”. Also view lectures from the Riordan clinic which has collected decades of experience and conducts research around the use of Intravenous Vitamin C.
Andrew Saul is a prolific researcher of the biological effects of Vitamin C and has authored many books on the subject. He has reviewed the history of vitamin C which you can view on his website: www.doctoryouself.com.

For more information:

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References:

Riordan HD, Jackson JA, Schultz, M.: Case Study: High-Dose Intravenous Vitamin C in the Treatment of a Patient With Adenocarcinoma of the Kidney. J. Orthomolecular Med, 1990, 5:1.

Jackson JA, Riordan HD, Hunninghake, R.E., Riordan NH: High Dose Intravenous Vitamin C and Long Term Survival of a Patient with Cancer of Head of the Pancreas. J. Orthomolecular Medicine, 1995; 10(2).

Riordan NH, Riordan HD, Meng, X., Li, Y., Jackson JA: Intravenous Ascorbate as a Tumor Cytotoxic Chemotherapeutic Agent. Medical Hypotheses, 1995 (44).

Riordan NH, Jackson JA, Riordan HD. Intravenous Vitamin C in a Terminal Cancer Patient. J. Orthomolecular Med, 1996, 11:2.

Riordan HD, et al. High-Dose Intravenous Vitamin C in the Treatment of a Patient with Renal Cell Carcinoma of the Kidney. J. Orthomolecular Med, 1998, 13:2.

Gonzalez MJ, Mora, E., Riordan NH, Riordan HD, Mojica, P.: Rethinking Vitamin C and Cancer: An Update on Nutritional Oncology. Cancer Prevention International, 1998, Vol. 3, 215-224.

Gonzalez MJ, Mora, E.M., Miranda-Massari, J.R., Matta, J., Riordan HD, Riordan NH: Inhibition of Human Breast Carcinoma Cell Proliferation by Ascorbate and Copper. Puerto Rico Health Sciences J, March 2002, 21:1.

Gonzalez MJ, Miranda-Massari, J.R., Mora, E.M., Jimenez, I.Z., Matos, M.I., Riordan HD, Casciari, J.J., Riordan NH, Rodriguez, M., Guzman, A.: Orthomolecular Oncology: a Mechanistic View of Intravenous Ascorbate’s Chemotherapeutic Activity. Puerto Rico Health Sciences J, March, 2002, 21:1.

Riordan HD, Hunninghake, R.E., Riordan NH, Jackson, J.A., Meng, X.L., Taylor, P., Casciari, J.J., Gonzalez MJ, Miranda-Massari, J.R., Mora, E.M., Norberto, R, Rivera, A. Intravenous Ascorbic Acid: Protocol for its Application and Use. Puerto Rico Health Sciences Journal, September 2003, 22:3.

Padayatty, S.J., Sun, H., Wang, Y., Riordan HD, Hewitt, S.M., Katz, A., Wesley, R.A., Levine, M. Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use. Annals of Internal Medicine, April 6, 2004, 140(7): 533-537.

 

Riordan HD, Riordan NH, Jackson JA, Casciari, J.J., Hunninghake, R, Gonzalez MJ, Mora, E.M., Miranda-Massari, J.R., Rosario, N., Rivera, A.: Intravenous Vitamin C as a Chemotherapy Agent: a Report on Clinical Cases. Puerto Rico Health Sciences J, June 2004, 23(2): 115-118.

Andrew Saul is the author of the books FIRE YOUR DOCTOR! How to be Independently Healthy (reader reviews at http://www.doctoryourself.com/review.html ) and DOCTOR YOURSELF: Natural Healing that Works. (reviewed at http://www.doctoryourself.com/saulbooks.html )

Further References:
  1. Agathocleous M., Meacham C. E., Burgess R. J., Piskounova E., Zhao Z., Crane G. M., et al. (2017). Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549 476–481. 10.1038/nature23876 [PMC free article] [PubMed] [CrossRef]
  2. Alexandrescu D. T., Dasanu C. A., Kauffman C. L. (2009). Acute scurvy during treatment with interleukin-2. Clin. Exp. Dermatol. 34 811–814. 10.1111/j.1365-2230.2008.03052.x [PubMed] [CrossRef]
  3. Anthony H. M., Schorah C. J. (1982). Severe hypovitaminosis C in lung-cancer patients: the utilization of vitamin C in surgical repair and lymphocyte-related host resistance. Br. J. Cancer 46354–367. 10.1038/bjc.1982.211 [PMC free article] [PubMed] [CrossRef]
  4. Belin S., Kaya F., Duisit G., Giacometti S., Ciccolini J., Fontes M. (2009). Antiproliferative effect of ascorbic acid is associated with the inhibition of genes necessary to cell cycle progression. PLoS One4:e4409. 10.1371/journal.pone.0004409 [PMC free article] [PubMed] [CrossRef]
  5. Blaschke K., Ebata K. T., Karimi M. M., Zepeda-Martinez J. A., Goyal P., Mahapatra S., et al. (2013). Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells.Nature 500 222–226. 10.1038/nature12362 [PMC free article] [PubMed] [CrossRef]
  6. Block G., Norkus E., Hudes M., Mandel S., Helzlsouer K. (2001). Which plasma antioxidants are most related to fruit and vegetable consumption? Am. J. Epidemiol. 154 1113–1118. 10.1093/aje/154.12.1113 [PubMed] [CrossRef]
  7. Camarena V., Wang G. (2016). The epigenetic role of vitamin C in health and disease. Cell Mol. Life Sci. 73 1645–1658. 10.1007/s00018-016-2145-x [PMC free article] [PubMed] [CrossRef]
  8. Cameron E. (1991). Protocol for the use of vitamin C in the treatment of cancer. Med. Hypotheses.36 190–194. 10.1016/0306-9877(91)90128-L [PubMed] [CrossRef]
  9. Cameron E., 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. 10.1016/0009-2797(74)90019-2 [PubMed] [CrossRef]
  10. Cameron E., Campbell A. (1991). Innovation vs. quality control: an ’unpublishable’ clinical trial of supplemental ascorbate in incurable cancer. Med. Hypotheses. 36 185–189. 10.1016/0306-9877(91)90127-K [PubMed] [CrossRef]
  11. Cameron E., Pauling L. (1976). 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. 10.1073/pnas.73.10.3685 [PMC free article] [PubMed] [CrossRef]
  12. Cameron E., Pauling L. (1978). 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. 10.1073/pnas.75.9.4538 [PMC free article] [PubMed] [CrossRef]
  13. Campbell E. J., Dachs G. U. (2014). Current limitations of murine models in oncology for ascorbate research. Front. Oncol. 4:282. 10.3389/fonc.2014.00282 [PMC free article] [PubMed] [CrossRef]
  14. Campbell E. J., Vissers M. C., Bozonet S., Dyer A., Robinson B. A., Dachs G. U. (2015). Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice. Cancer Med. 4 303–314. 10.1002/cam4.349 [PMC free article] [PubMed] [CrossRef]
  15. Campbell E. J., Vissers M. C., Dachs G. U. (2016a). Ascorbate availability affects tumor implantation-take rate and increases tumor rejection in Gulo-/- mice. Hypoxia (Auckl.) 4 41–52.[PMC free article] [PubMed]
  16. Campbell E. J., Vissers M. C., Wohlrab C., Hicks K. O., Strother R. M., Bozonet S. M., et al. (2016b). Pharmacokinetic and anti-cancer properties of high dose ascorbate in solid tumours of ascorbate-dependent mice. Free Radic. Biol. Med. 99 451–462. 10.1016/j.freeradbiomed.2016.08.027 [PubMed] [CrossRef]
  17. Carr A., Frei B. (1999a). Does vitamin C act as a pro-oxidant under physiological conditions?FASEB J. 13 1007–1024. [PubMed]
  18. Carr A., Wohlrab C., Young P., Bellomo R. (2018). Stability of intravenous vitamin C solutions: a technical report. Crit. Care Resuscita (in press). [PubMed]
  19. Carr A. C., Frei B. (1999b). Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am. J. Clin. Nutr. 69 1086–1107. [PubMed]
  20. Carr A. C., Maggini S. (2017). Vitamin C and immune function. Nutrients 9:E1211. 10.3390/nu9111211 [PMC free article] [PubMed] [CrossRef]
  21. Carr A. C., McCall C. (2017). The role of vitamin C in the treatment of pain: new insights. J. Transl. Med. 15:77. 10.1186/s12967-017-1179-7 [PMC free article] [PubMed] [CrossRef]
  22. Carr A. C., Vissers M. C. M., Cook J. S. (2014). The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality of life. Front. Oncol. 4:283. 10.3389/fonc.2014.00283[PMC free article] [PubMed] [CrossRef]
  23. Casciari J. J., Riordan H. D., Miranda-Massari J. R., Gonzalez M. J. (2005). Effects of high dose ascorbate administration on L-10 tumor growth in guinea pigs. P R Health Sci. J. 24 145–150. [PubMed]
  24. Cha J., Roomi M. W., Ivanov V., Kalinovsky T., Niedzwiecki A., Rath M. (2011). Ascorbate depletion increases growth and metastasis of melanoma cells in vitamin C deficient mice. Exp. Oncol. 33 226–230. [PubMed]
  25. Cha J., Roomi M. W., Ivanov V., Kalinovsky T., Niedzwiecki A., Rath M. (2013). Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice. Int. J. Oncol. 42 55–64. 10.3892/ijo.2012.1712 [PMC free article][PubMed] [CrossRef]
  26. Cha J., Roomi M. W., Kalinovsky T., Niedzwiecki A., Rath M. (2016). Lipoprotein(a) and vitamin C impair development of breast cancer tumors in Lp(a)+, Gulo-/- mice. Int. J. Oncol. 49 895–902. 10.3892/ijo.2016.3597 [PMC free article] [PubMed] [CrossRef]
  27. Chen M. F., Yang C. M., Su C. M., Hu M. L. (2014). Vitamin C protects against cisplatin-induced nephrotoxicity and damage without reducing its effectiveness in C57BL/6 mice xenografted with Lewis lung carcinoma. Nutr. Cancer 66 1085–1091. 10.1080/01635581.2014.948211 [PubMed] [CrossRef]
  28. Chen P., Stone J., Sullivan G., Drisko J. A., Chen Q. (2011). Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models.Free Radic. Biol. Med. 51 681–687. 10.1016/j.freeradbiomed.2011.05.031 [PubMed] [CrossRef]
  29. Chen Q., Espey M. G., Krishna M. C., Mitchell J. B., Corpe C. P., Buettner G. R., et al. (2005). 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. 102 13604–13609. 10.1073/pnas.0506390102 [PMC free article] [PubMed] [CrossRef]
  30. Chen Q., Espey M. G., Sun A. Y., Lee J. H., Krishna M. C., Shacter E., et al. (2007). 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. 10.1073/pnas.0702854104[PMC free article] [PubMed] [CrossRef]
  31. Chen Q., Espey M. G., Sun A. Y., Pooput C., Kirk K. L., Krishna M. C., et al. (2008). 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. 10.1073/pnas.0804226105 [PMC free article][PubMed] [CrossRef]
  32. Chirino Y. I., Pedraza-Chaverri J. (2009). Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp. Toxicol. Pathol. 61 223–242. 10.1016/j.etp.2008.09.003 [PubMed] [CrossRef]
  33. Choi M. A., Kim B. S., Yu R. (1999). Serum antioxidative vitamin levels and lipid peroxidation in gastric carcinoma patients. Cancer Lett. 136 89–93. 10.1016/S0304-3835(98)00312-7 [PubMed] [CrossRef]
  34. Cieslak J. A., Cullen J. J. (2015). Treatment of pancreatic cancer with pharmacological ascorbate.Curr. Pharm. Biotechnol. 16 759–770. 10.2174/138920101609150715135921 [PMC free article][PubMed] [CrossRef]
  35. Cieslak J. A., Sibenaller Z. A., Walsh S. A., Ponto L. L., Du J., Sunderland J. J., et al. (2016). Fluorine-18-Labeled thymidine positron emission tomography (FLT-PET) as an index of cell proliferation after pharmacological ascorbate-based therapy. Radiat. Res. 185 31–38. 10.1667/RR14203.1 [PMC free article] [PubMed] [CrossRef]
  36. Cimmino L., Dolgalev I., Wang Y., Yoshimi A., Martin G. H., Wang J., et al. (2017). Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170 1079.e20–1095.e20. 10.1016/j.cell.2017.07.032 [PMC free article] [PubMed] [CrossRef]
  37. Clement M. V., Ramalingam J., Long L. H., Halliwell B. (2001). The in vitro cytotoxicity of ascorbate depends on the culture medium used to perform the assay and involves hydrogen peroxide.Antioxid. Redox Signal. 3 157–163. 10.1089/152308601750100687 [PubMed] [CrossRef]
  38. Cossey L. N., Rahim F., Larsen C. P. (2013). Oxalate nephropathy and intravenous vitamin C. Am. J. Kidney Dis. 61 1032–1035. 10.1053/j.ajkd.2013.01.025 [PubMed] [CrossRef]
  39. Creagan E. T., Moertel C. G., O’Fallon J. R., Schutt A. J., O’Connell M. J., Rubin J., et al. (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. 10.1056/NEJM197909273011303 [PubMed] [CrossRef]
  40. D’Andrea G. M. (2005). Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J. Clin. 55 319–321. 10.3322/canjclin.55.5.319 [PubMed] [CrossRef]
  41. de Grooth H. J., Manubulu-Choo W. P., Zandvliet A. S., Spoelstra-de Man A. M. E., Girbes A. R., Swart E. L., et al. (2018). Vitamin-C pharmacokinetics in critically ill patients: a randomized trial of four intravenous regimens. Chest 153 1368–1377. 10.1016/j.chest.2018.02.025 [PubMed] [CrossRef]
  42. Doskey C. M., Buranasudja V., Wagner B. A., Wilkes J. G., Du J., Cullen J. J., et al. (2016). Tumor cells have decreased ability to metabolize H2O2: implications for pharmacological ascorbate in cancer therapy. Redox Biol. 10 274–284. 10.1016/j.redox.2016.10.010 [PMC free article] [PubMed] [CrossRef]
  43. Du J., Cieslak J. A., III, Welsh J. L., Sibenaller Z. A., Allen B. G., Wagner B. A., et al. (2015). Pharmacological ascorbate radiosensitizes pancreatic cancer. Cancer Res. 75 3314–3326. 10.1158/0008-5472.CAN-14-1707 [PMC free article] [PubMed] [CrossRef]
  44. Du J., Cullen J. J., Buettner G. R. (2012). Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim. Biophys. Acta 1826 443–457. 10.1016/j.bbcan.2012.06.003 [PMC free article][PubMed] [CrossRef]
  45. Du J., Martin S. M., Levine M., Wagner B. A., Buettner G. R., Wang S. H., et al. (2010). Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin. Cancer Res. 16 509–520. 10.1158/1078-0432.CCR-09-1713 [PMC free article] [PubMed] [CrossRef]
  46. Ebata K. T., Mesh K., Liu S., Bilenky M., Fekete A., Acker M. G., et al. (2017). Vitamin C induces specific demethylation of H3K9me2 in mouse embryonic stem cells via Kdm3a/b. Epigenet. Chromat. 10:36. 10.1186/s13072-017-0143-3 [PMC free article] [PubMed] [CrossRef]
  47. Emri S., Kilickap S., Kadilar C., Halil M. G., Akay H., Besler T. (2012). Serum levels of alpha-tocopherol, vitamin C, beta-carotene, and retinol in malignant pleural mesothelioma. Asian Pac. J Cancer Prev. 13 3025–3029. 10.7314/APJCP.2012.13.7.3025 [PubMed] [CrossRef]
  48. Englard S., Seifter S. (1986). The biochemical functions of ascorbic acid. Annu. Rev. Nutr. 6 365–406. 10.1146/annurev.nu.06.070186.002053 [PubMed] [CrossRef]
  49. Espey M. G., Chen P., Chalmers B., Drisko J., Sun A. Y., Levine M., et al. (2011). Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic. Biol. Med. 50 1610–1619. 10.1016/j.freeradbiomed.2011.03.007 [PMC free article] [PubMed] [CrossRef]
  50. Fain O., Mathieu E., Thomas M. (1998). Scurvy in patients with cancer. BMJ. 316 1661–1662. 10.1136/bmj.316.7145.1661 [PMC free article] [PubMed] [CrossRef]
  51. Fritz H., Flower G., Weeks L., Cooley K., Callachan M., McGowan J., et al. (2014). Intravenous vitamin C and cancer: a systematic review. Integr. Cancer Ther. 13 280–300. 10.1177/1534735414534463 [PubMed] [CrossRef]
  52. Fujita K., Shinpo K., Yamada K., Sato T., Niimi H., Shamoto M., et al. (1982). Reduction of adriamycin toxicity by ascorbate in mice and guinea pigs. Cancer Res. 42 309–316. [PubMed]
  53. Gao P., Zhang H., Dinavahi R., Li F., Xiang Y., Raman V., et al. (2007). HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12 230–238. 10.1016/j.ccr.2007.08.004[PMC free article] [PubMed] [CrossRef]
  54. Gillberg L., Orskov A. D., Liu M., Harslof L. B. S., Jones P. A., Gronbaek K. (2017). Vitamin C – A new player in regulation of the cancer epigenome. Semin. Cancer Biol. 51 59–67. 10.1016/j.semcancer.2017.11.001 [PubMed] [CrossRef]
  55. Goncalves T. L., Benvegnu D. M., Bonfanti G., Frediani A. V., Rocha J. B. (2009). Delta-Aminolevulinate dehydratase activity and oxidative stress during melphalan and cyclophosphamide-BCNU-etoposide (CBV) conditioning regimens in autologous bone marrow transplantation patients.Pharmacol. Res. 59 279–284. 10.1016/j.phrs.2008.12.005 [PubMed] [CrossRef]
  56. Gonzalez M. J., Miranda Massari J. R., Duconge J., Riordan N. H., Ichim T. (2012). Schedule dependence in cancer therapy: intravenous vitamin C and the systemic saturation hypothesis. J. Orthomol. Med. 27 9–12. [PMC free article] [PubMed]
  57. Grasso C., Fabre M. S., Collis S. V., Castro M. L., Field C. S., Schleich N., et al. (2014). Pharmacological doses of daily ascorbate protect tumors from radiation damage after a single dose of radiation in an intracranial mouse glioma model. Front. Oncol. 4:356. 10.3389/fonc.2014.00356[PMC free article] [PubMed] [CrossRef]
  58. Guemouri L., Artur Y., Herbeth B., Jeandel C., Cuny G., Siest G. (1991). Biological variability of superoxide dismutase, glutathione peroxidase, and catalase in blood. Clin. Chem. 37 1932–1937. [PubMed]
  59. Gunes-Bayir A., Kiziltan H. S. (2015). Palliative vitamin C application in patients with radiotherapy-resistant bone metastases: a retrospective study. Nutr. Cancer 67 921–925. 10.1080/01635581.2015.1055366 [PubMed] [CrossRef]
  60. Gupta A., Bhatt M. L., Misra M. K. (2009). Lipid peroxidation and antioxidant status in head and neck squamous cell carcinoma patients. Oxid. Med. Cell Longev. 2 68–72. 10.4161/oxim.2.2.8160 [PMC free article] [PubMed] [CrossRef]
  61. Gustafson C. B., Yang C., Dickson K. M., Shao H., Van Booven D., Harbour J. W., et al. (2015). Epigenetic reprogramming of melanoma cells by vitamin C treatment. Clin. Epigenet. 7:51. 10.1186/s13148-015-0087-z [PMC free article] [PubMed] [CrossRef]
  62. Haffner M. C., Chaux A., Meeker A. K., Esopi D. M., Gerber J., Pellakuru L. G., et al. (2011). Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget 2 627–637. 10.18632/oncotarget.316[PMC free article] [PubMed] [CrossRef]
  63. Harris H. R., Orsini N., Wolk A. (2014). Vitamin C and survival among women with breast cancer: a meta-analysis. Eur. J Cancer 50 1223–1231. 10.1016/j.ejca.2014.02.013 [PubMed] [CrossRef]
  64. Herst P. M., Broadley K. W., Harper J. L., McConnell M. J. (2012). Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radic. Biol. Med. 52 1486–1493. 10.1016/j.freeradbiomed.2012.01.021 [PubMed] [CrossRef]
  65. Hirota K., Semenza G. L. (2005). Regulation of hypoxia-inducible factor 1 by prolyl and asparaginyl hydroxylases. Biochem. Biophys. Res. Commun. 338 610–616. 10.1016/j.bbrc.2005.08.193 [PubMed] [CrossRef]
  66. Hirsila M., Koivunen P., Gunzler V., Kivirikko K. I., Myllyharju J. (2003). Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem. 278 30772–30780. 10.1074/jbc.M304982200 [PubMed] [CrossRef]
  67. Hoffer L. J., Levine M., Assouline S., Melnychuk D., Padayatty S. J., Rosadiuk K., et al. (2008). Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann. Oncol. 19 1969–1974. 10.1093/annonc/mdn377 [PubMed] [CrossRef]
  68. Hoffer L. J., Robitaille L., Zakarian R., Melnychuk D., Kavan P., Agulnik J., et al. (2015). High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a Phase I-II clinical trial. PLoS One 10:e0120228. 10.1371/journal.pone.0120228 [PMC free article][PubMed] [CrossRef]
  69. Hosokawa Y., Monzen S., Yoshino H., Terashima S., Nakano M., Toshima K., et al. (2015). Effects of Xray irradiation in combination with ascorbic acid on tumor control. Mol. Med. Rep. 12 5449–5454. 10.3892/mmr.2015.4108 [PubMed] [CrossRef]
  70. Huijskens M. J., Wodzig W. K., Walczak M., Germeraad W. T., Bos G. M. (2016). Ascorbic acid serum levels are reduced in patients with hematological malignancies. Results Immunol. 6 8–10. 10.1016/j.rinim.2016.01.001 [PMC free article] [PubMed] [CrossRef]
  71. Hunnisett A., Davies S., McLaren-Howard J., Gravett P., Finn M., Gueret-Wardle D. (1995). Lipoperoxides as an index of free radical activity in bone marrow transplant recipients. Prelimin. Obs. Biol. Trace Elem. Res. 47 125–132. 10.1007/BF02790109 [PubMed] [CrossRef]
  72. Jonas C. R., Puckett A. B., Jones D. P., Griffith D. P., Szeszycki E. E., Bergman G. F., et al. (2000). Plasma antioxidant status after high-dose chemotherapy: a randomized trial of parenteral nutrition in bone marrow transplantation patients. Am. J. Clin. Nutr. 72 181–189. 10.1093/ajcn/72.1.181 [PubMed] [CrossRef]
  73. Jozwiak P., Ciesielski P., Zaczek A., Lipinska A., Pomorski L., Wieczorek M., et al. (2017). Expression of hypoxia inducible factor 1alpha and 2alpha and its association with vitamin C level in thyroid lesions. J. Biomed. Sci. 24:83. 10.1186/s12929-017-0388-y [PMC free article] [PubMed] [CrossRef]
  74. Kahn S. A., Lentz C. W. (2015). Fictitious hyperglycemia: point-of-care glucose measurement is inaccurate during high-dose vitamin C infusion for burn shock resuscitation. J. Burn Care Res.. 36e67–e71. 10.1097/BCR.0000000000000141 [PubMed] [CrossRef]
  75. Kalita S., Verma A. K., Prasad S. B. (2014). Chlorambucil and ascorbic acid-mediated anticancer activity and hematological toxicity in Dalton’s ascites lymphoma-bearing mice. Indian J. Exp. Biol.52 112–124. [PubMed]
  76. Kawada H., Sawanobori M., Tsuma-Kaneko M., Wasada I., Miyamoto M., Murayama H., et al. (2014). Phase I clinical trial of intravenous L-ascorbic acid following salvage chemotherapy for relapsed B-cell non-Hodgkin’s lymphoma. Tokai J. Exp. Clin. Med. 39 111–115. [PubMed]
  77. Khanzode S. S., Khanzode S. D., Dakhale G. N. (2003). Serum and plasma concentration of oxidant and antioxidants in patients of Helicobacter pylori gastritis and its correlation with gastric cancer.Cancer Lett. 195 27–31. 10.1016/S0304-3835(03)00147-2 [PubMed] [CrossRef]
  78. Khanzode S. S., Muddeshwar M. G., Khanzode S. D., Dakhale G. N. (2004). Antioxidant enzymes and lipid peroxidation in different stages of breast cancer. Free Radic. Res. 38 81–85. 10.1080/01411590310001637066 [PubMed] [CrossRef]
  79. Kiziltan H. S., Bayir A. G., Demirtas M., Meral I., Taspinar O., Eris A. H., et al. (2014). Ascorbic-acid treatment for progressive bone metastases after radiotherapy: a pilot study. Altern. Ther. Health Med. 20(Suppl. 2), 16–20. [PubMed]
  80. Klose R. J., Kallin E. M., Zhang Y. (2006). JmjC-domain-containing proteins and histone demethylation. Nat. Rev. Genet. 7 715–727. 10.1038/nrg1945 [PubMed] [CrossRef]
  81. Koivunen P., Hirsila M., Gunzler V., Kivirikko K. I., Myllyharju J. (2004). Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J. Biol. Chem. 279 9899–9904. 10.1074/jbc.M312254200 [PubMed] [CrossRef]
  82. Kroeze L. I., van der Reijden B. A., Jansen J. H. (2015). 5-hydroxymethylcytosine: an epigenetic mark frequently deregulated in cancer. Biochim. Biophys. Acta 1855 144–154. 10.1016/j.bbcan.2015.01.001 [PubMed] [CrossRef]
  83. Kudo Y., Tateishi K., Yamamoto K., Yamamoto S., Asaoka Y., Ijichi H., et al. (2012). Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci. 103670–676. 10.1111/j.1349-7006.2012.02213.x [PubMed] [CrossRef]
  84. Kuiper C., Dachs G. U., Munn D., Currie M. J., Robinson B. A., Pearson J. F., et al. (2014a). Increased tumor ascorbate is associated with extended disease-free survival and decreased hypoxia-inducible factor-1 activation in human colorectal cancer. Front. Oncol. 4:10. 10.3389/fonc.2014.00010 [PMC free article] [PubMed] [CrossRef]
  85. Kuiper C., Vissers M. C., Hicks K. O. (2014b). Pharmacokinetic modeling of ascorbate diffusion through normal and tumor tissue. Free Radic. Biol. Med. 77 340–352. 10.1016/j.freeradbiomed.2014.09.023 [PubMed] [CrossRef]
  86. Kuiper C., Molenaar I. G., Dachs G. U., Currie M. J., Sykes P. H., Vissers M. C. (2010). Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res. 70 5749–5758. 10.1158/0008-5472.CAN-10-0263 [PubMed] [CrossRef]
  87. Kuiper C., Vissers M. C. (2014). Ascorbate as a co-factor for Fe- and 2-oxoglutarate dependent dioxygenases: physiological activity in tumor growth and progression. Front. Oncol. 4:359. 10.3389/fonc.2014.00359 [PMC free article] [PubMed] [CrossRef]
  88. Lawenda B. D., Kelly K. M., Ladas E. J., Sagar S. M., Vickers A., Blumberg J. B. (2008). Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J. Natl. Cancer Inst. 100 773–783. 10.1093/jnci/djn148 [PubMed] [CrossRef]
  89. Lawton J. M., Conway L. T., Crosson J. T., Smith C. L., Abraham P. A. (1985). Acute oxalate nephropathy after massive ascorbic acid administration. Arch. Intern. Med. 145 950–951. 10.1001/archinte.1985.00360050220044 [PubMed] [CrossRef]
  90. Lee J., Lee G., Park J. H., Lee S., Yeom C. H., Na B., et al. (2012). Proteomic analysis of tumor tissue in CT-26 implanted BALB/C mouse after treatment with ascorbic acid. Cell. Mol. Biol. Lett.17 62–76. 10.2478/s11658-011-0035-7 [PMC free article] [PubMed] [CrossRef]
  91. Levine M., Conry-Cantilena C., Wang Y., Welch R. W., Washko P. W., Dhariwal K. R., et al. (1996). Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance.Proc. Natl. Acad. Sci. U.S.A. 93 3704–3709. 10.1073/pnas.93.8.3704 [PMC free article] [PubMed] [CrossRef]
  92. Lian C. G., Xu Y., Ceol C., Wu F., Larson A., Dresser K., et al. (2012). Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 150 1135–1146. 10.1016/j.cell.2012.07.033 [PMC free article] [PubMed] [CrossRef]
  93. Liu M., Ohtani H., Zhou W., Orskov A. D., Charlet J., Zhang Y. W., et al. (2016). Vitamin C increases viral mimicry induced by 5-aza-2′-deoxycytidine. Proc. Natl. Acad. Sci. U.S.A. 113 10238–10244. 10.1073/pnas.1612262113 [PMC free article] [PubMed] [CrossRef]
  94. Low F. M., Hampton M. B., Winterbourn C. C. (2008). Peroxiredoxin 2 and peroxide metabolism in the erythrocyte. Antioxid. Redox Signal. 10 1621–1630. 10.1089/ars.2008.2081 [PubMed] [CrossRef]
  95. Lykkesfeldt J., Poulsen H. E. (2010). Is vitamin C supplementation beneficial? Lessons learned from randomised controlled trials. Br. J. Nutr. 103 1251–1259. 10.1017/S0007114509993229 [PubMed] [CrossRef]
  96. Ma Y., Chapman J., Levine M., Polireddy K., Drisko J., Chen Q. (2014). High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci. Transl. Med. 6:222ra18. 10.1126/scitranslmed.3007154 [PubMed] [CrossRef]
  97. Ma Y., Sullivan G. G., Schrick E., Choi I. Y., He Z., Lierman J., et al. (2013). A convenient method for measuring blood ascorbate concentrations in patients receiving high-dose intravenous ascorbate.J. Am. Coll Nutr. 32 187–193. 10.1080/07315724.2013.791167 [PMC free article] [PubMed] [CrossRef]
  98. Mahdavi R., Faramarzi E., Seyedrezazadeh E., Mohammad-Zadeh M., Pourmoghaddam M. (2009). Evaluation of oxidative stress, antioxidant status and serum vitamin C levels in cancer patients. Biol. Trace Elem. Res. 130 1–6. 10.1007/s12011-008-8309-2 [PubMed] [CrossRef]
  99. Mamede A. C., Pires A. S., Abrantes A. M., Tavares S. D., Goncalves A. C., Casalta-Lopes J. E., et al. (2012). Cytotoxicity of ascorbic acid in a human colorectal adenocarcinoma cell line (WiDr): in vitro and in vivo studies. Nutr. Cancer 64 1049–1057. 10.1080/01635581.2012.713539 [PubMed] [CrossRef]
  100. Manning J., Mitchell B., Appadurai D. A., Shakya A., Pierce L. J., Wang H., et al. (2013). Vitamin C promotes maturation of T-cells. Antioxid. Redox Signal. 19 2054–2067. 10.1089/ars.2012.4988[PMC free article] [PubMed] [CrossRef]
  101. Marcus S. L., Petrylak D. P., Dutcher J. P., Paietta E., Ciobanu N., Strauman J., et al. (1991). Hypovitaminosis C in patients treated with high-dose interleukin 2 and lymphokine-activated killer cells. Am. J. Clin. Nutr. 54(6 Suppl.),1292S–1297S. 10.1093/ajcn/54.6.1292s [PubMed] [CrossRef]
  102. Mayland C. R., Bennett M. I., Allan K. (2005). Vitamin C deficiency in cancer patients. Palliat Med.19 17–20. 10.1191/0269216305pm970oa [PubMed] [CrossRef]
  103. Mehdi W. A., Zainulabdeen J. A., Mehde A. A. (2013). Investigation of the antioxidant status in multiple myeloma patients: effects of therapy. Asian Pac. J. Cancer Prev. 14 3663–3667. 10.7314/APJCP.2013.14.6.3663 [PubMed] [CrossRef]
  104. Mikirova N., Casciari J., Riordan N., Hunninghake R. (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. 10.1186/1479-5876-11-191 [PMC free article][PubMed] [CrossRef]
  105. Mikirova N., Casciari J., Rogers A., Taylor P. (2012). Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J. Transl. Med. 10 189. 10.1186/1479-5876-10-189[PMC free article] [PubMed] [CrossRef]
  106. Mikirova N., Riordan N., Casciari J. (2016). Modulation of cytokines in cancer patients by intravenous ascorbate therapy. Med. Sci. Monit. 22 14–25. 10.12659/MSM.895368 [PMC free article] [PubMed] [CrossRef]
  107. Mingay M., Chaturvedi A., Bilenky M., Cao Q., Jackson L., Hui T., et al. (2017). Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia. Leukemia 32 11–20. 10.1038/leu.2017.171 [PMC free article] [PubMed] [CrossRef]
  108. Minor E. A., Court B. L., Young J. I., Wang G. (2013). Ascorbate induces Ten-eleven translocation (Tet) methylcytosine dioxygenase-mediated generation of 5-hydroxymethylcytosine. J. Biol. Chem.288 13669–13674. 10.1074/jbc.C113.464800 [PMC free article] [PubMed] [CrossRef]
  109. Moertel C. G., Fleming T. R., Creagan E. T., Rubin J., O’Connell M. J., Ames M. M. (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. 10.1056/NEJM198501173120301 [PubMed] [CrossRef]
  110. Monti D. A., Mitchell E., Bazzan A. J., Littman S., Zabrecky G., Yeo C. J., et al. (2012). Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS One 7:e29794. 10.1371/journal.pone.0029794[PMC free article] [PubMed] [CrossRef]
  111. Muhlhofer A., Mrosek S., Schlegel B., Trommer W., Rozario F., Bohles H., et al. (2004). High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers. Eur. J. Clin. Nutr. 58 1151–1158. 10.1038/sj.ejcn.1601943 [PubMed] [CrossRef]
  112. Murata A., Morishige F., 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. [PubMed]
  113. Nannya Y., Shinohara A., Ichikawa M., Kurokawa M. (2014). Serial profile of vitamins and trace elements during the acute phase of allogeneic stem cell transplantation. Biol. Blood Marrow Transplant. 20 430–434. 10.1016/j.bbmt.2013.12.554 [PubMed] [CrossRef]
  114. Nielsen T. K., Hojgaard M., Andersen J. T., Jorgensen N. R., Zerahn B., Kristensen B., et al. (2017). Weekly ascorbic acid infusion in castration-resistant prostate cancer patients: a single-arm phase II trial. Transl. Androl. Urol. 6 517–528. 10.21037/tau.2017.04.42 [PMC free article] [PubMed] [CrossRef]
  115. Nielsen T. K., Hojgaard M., Andersen J. T., Poulsen H. E., Lykkesfeldt J., Mikines K. J. (2015). Elimination of ascorbic acid after high-dose infusion in prostate cancer patients: a pharmacokinetic evaluation. Basic Clin. Pharmacol. Toxicol. 116 343–348. 10.1111/bcpt.12323 [PubMed] [CrossRef]
  116. Oak A. S., Jaleel T., Fening K., Pavlidakey P. G., Sami N. (2016). A case of scurvy associated with nilotinib. J. Cutan Pathol. 43 725–726. 10.1111/cup.12715 [PubMed] [CrossRef]
  117. Padayatty S. J., Riordan H. D., Hewitt S. M., Katz A., Hoffer L. J., Levine M. (2006). Intravenously administered vitamin C as cancer therapy: three cases. CMAJ 174 937–942. 10.1503/cmaj.050346[PMC free article] [PubMed] [CrossRef]
  118. Padayatty S. J., Sun A. Y., Chen Q., Espey M. G., Drisko J., Levine M. (2010). Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One 5:e11414. 10.1371/journal.pone.0011414 [PMC free article] [PubMed] [CrossRef]
  119. Padayatty S. J., Sun H., Wang Y., Riordan H. D., Hewitt S. M., Katz A., et al. (2004). Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann. Int. Med. 140 533–537. 10.7326/0003-4819-140-7-200404060-00010 [PubMed] [CrossRef]
  120. Park J. H., Davis K. R., Lee G., Jung M., Jung Y., Park J., et al. (2012). Ascorbic acid alleviates toxicity of paclitaxel without interfering with the anticancer efficacy in mice. Nutr. Res. 32 873–883. 10.1016/j.nutres.2012.09.011 [PubMed] [CrossRef]
  121. Park S., Ahn E. S., Lee S., Jung M., Park J. H., Yi S. Y., et al. (2009). Proteomic analysis reveals upregulation of RKIP in S-180 implanted BALB/C mouse after treatment with ascorbic acid. J. Cell Biochem. 106 1136–1145. 10.1002/jcb.22097 [PubMed] [CrossRef]
  122. Parrow N. L., Leshin J. A., Levine M. (2013). Parenteral ascorbate as a cancer therapeutic: a reassessment based on pharmacokinetics. Antioxid. Redox Signal. 19 2141–2156. 10.1089/ars.2013.5372 [PMC free article] [PubMed] [CrossRef]
  123. Polireddy K., Dong R., Reed G., Yu J., Chen P., Williamson S., et al. (2017). High dose parenteral ascorbate inhibited pancreatic cancer growth and metastasis: mechanisms and a Phase I/IIa study.Sci. Rep. 7:17188. 10.1038/s41598-017-17568-8 [PMC free article] [PubMed] [CrossRef]
  124. Pollard H. B., Levine M. A., Eidelman O., Pollard M. (2010). Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In Vivo 24249–255. [PubMed]
  125. Pullar J. M., Bayer S., Carr A. C. (2018). Appropriate handling, processing and analysis of blood samples is essential to avoid oxidation of vitamin C to dehydroascorbic acid. Antioxidants 7:E29. 10.3390/antiox7020029 [PMC free article] [PubMed] [CrossRef]
  126. Quinn J., Gerber B., Fouche R., Kenyon K., Blom Z., Muthukanagaraj P. (2017). Effect of high-dose vitamin C infusion in a glucose-6-phosphate dehydrogenase-deficient patient. Case Rep. Med.2017:5202606. 10.1155/2017/5202606 [PMC free article] [PubMed] [CrossRef]
  127. Ramaswamy G., Krishnamoorthy L. (1996). Serum carotene, vitamin A, and vitamin C levels in breast cancer and cancer of the uterine cervix. Nutr. Cancer 25 173–177. 10.1080/01635589609514439 [PubMed] [CrossRef]
  128. Rasheed M., Roberts C. H., Gupta G., Fisher B. J., Leslie K., Simmons G. L., et al. (2017). Low plasma vitamin C levels in patients undergoing stem cell transplantation (Abstract). Biol. Blood Marrow Transpl. 23 S225–S226. 10.1016/j.bbmt.2016.12.446 [CrossRef]
  129. Raymond Y. C., Glenda C. S., Meng L. K. (2016). Effects of high doses of vitamin C on cancer patients in singapore: nine cases. Integr. Cancer Ther. 15 197–204. 10.1177/1534735415622010[PMC free article] [PubMed] [CrossRef]
  130. Rees D. C., Kelsey H., Richards J. D. (1993). Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ 306 841–842. 10.1136/bmj.306.6881.841 [PMC free article] [PubMed] [CrossRef]
  131. Reuter S., Gupta S. C., Chaturvedi M. M., Aggarwal B. B. (2010). Oxidative stress, inflammation, and cancer: how are they linked? Free Radic. Biol. Med. 49 1603–1616. 10.1016/j.freeradbiomed.2010.09.006 [PMC free article] [PubMed] [CrossRef]
  132. Riordan H. D., Casciari J. J., Gonzalez M. J., Riordan N. H., Miranda-Massari J. R., Taylor P., et al. (2005). A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. PR Health Sci. J. 24 269–276. [PubMed]
  133. Riordan H. D., Riordan N. H., Jackson J. A., Casciari J. J., Hunninghake R., Gonzalez M. J., et al. (2004). Intravenous vitamin C as a chemotherapy agent: a report on clinical cases. PR Health Sci. J.23 115–118. [PubMed]
  134. Robitaille L., Mamer O. A., Miller W. H., Jr., Levine M., Assouline S., Melnychuk D., et al. (2009). Oxalic acid excretion after intravenous ascorbic acid administration. Metabolism 58 263–269. 10.1016/j.metabol.2008.09.023 [PMC free article] [PubMed] [CrossRef]
  135. Rouleau L., Antony A. N., Bisetto S., Newberg A., Doria C., Levine M., et al. (2016). Synergistic effects of ascorbate and sorafenib in hepatocellular carcinoma: new insights into ascorbate cytotoxicity. Free Radic. Biol. Med. 95 308–322. 10.1016/j.freeradbiomed.2016.03.031[PMC free article] [PubMed] [CrossRef]
  136. Savini I., Rossi A., Pierro C., Avigliano L., Catani M. V. (2008). SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids 34 347–355. 10.1007/s00726-007-0555-7 [PubMed] [CrossRef]
  137. Schoenfeld J. D., Sibenaller Z. A., Mapuskar K. A., Wagner B. A., Cramer-Morales K. L., Furqan M., et al. (2017). O2- and H2O2-Mediated Disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM Cancer cells to pharmacological ascorbate. Cancer Cell. 31487.e8–500.e8. 10.1016/j.ccell.2017.02.018 [PMC free article] [PubMed] [CrossRef]
  138. Seely D., Stempak D., Baruchel S. (2007). A strategy for controlling potential interactions between natural health products and chemotherapy: a review in pediatric oncology. J. Pediatr. Hematol. Oncol. 29 32–47. 10.1097/MPH.0b013e3180310521 [PubMed] [CrossRef]
  139. Serrano O. K., Parrow N. L., Violet P. C., Yang J., Zornjak J., Basseville A., et al. (2015). Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model. Free Radic. Biol. Med. 87193–203. 10.1016/j.freeradbiomed.2015.06.032 [PubMed] [CrossRef]
  140. Sestili P., Brandi G., Brambilla L., Cattabeni F., Cantoni O. (1996). Hydrogen peroxide mediates the killing of U937 tumor cells elicited by pharmacologically attainable concentrations of ascorbic acid: cell death prevention by extracellular catalase or catalase from cocultured erythrocytes or fibroblasts.J. Pharmacol. Exp. Ther. 277 1719–1725. [PubMed]
  141. Sharma A., Tripathi M., Satyam A., Kumar L. (2009). Study of antioxidant levels in patients with multiple myeloma. Leuk Lymphoma 50 809–815. 10.1080/10428190902802323 [PubMed] [CrossRef]
  142. Shenoy N., Bhagat T., Nieves E., Stenson M., Lawson J., Choudhary G. S., et al. (2017). Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells.Blood Cancer J. 7:e587. 10.1038/bcj.2017.65 [PMC free article] [PubMed] [CrossRef]
  143. Shinozaki K., Hosokawa Y., Hazawa M., Kashiwakura I., Okumura K., Kaku T., et al. (2011). Ascorbic acid enhances radiation-induced apoptosis in an HL60 human leukemia cell line. J. Radiat. Res. 52 229–237. 10.1269/jrr.10089 [PubMed] [CrossRef]
  144. Simone C. B., II, Simone N. L., Simone V. (2007). Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1. Altern. Ther. Health Med. 13 22–28. [PubMed]
  145. Song M. H., Nair V. S., Oh K. I. (2017). Vitamin C enhances the expression of IL17 in a Jmjd2-dependent manner. BMB Rep. 50 49–54. 10.5483/BMBRep.2017.50.1.193 [PMC free article][PubMed] [CrossRef]
  146. Stephenson C. M., Levin R. D., Spector T., Lis C. G. (2013). Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother. Pharmacol. 72 139–146. 10.1007/s00280-013-2179-9[PMC free article] [PubMed] [CrossRef]
  147. Takahashi H., Mizuno H., Yanagisawa A. (2012). High-dose intravenous vitamin C improves quality of life in cancer patients. Personal. Med. Universe. 2 49–53. 10.1016/j.pmu.2012.05.008 [CrossRef]
  148. Takemura Y., Satoh M., Satoh K., Hamada H., Sekido Y., Kubota S. (2010). High dose of ascorbic acid induces cell death in mesothelioma cells. Biochem. Biophys. Res. Commun. 394 249–253. 10.1016/j.bbrc.2010.02.012 [PubMed] [CrossRef]
  149. Tang Z., Du X., Louie R. F., Kost G. J. (2000). Effects of drugs on glucose measurements with handheld glucose meters and a portable glucose analyzer. Am. J. Clin. Pathol. 113 75–86. 10.1309/QAW1-X5XW-BVRQ-5LKQ [PubMed] [CrossRef]
  150. Torun M., Yardim S., Gonenc A., Sargin H., Menevse A., Simsek B. (1995). Serum beta-carotene, vitamin E, vitamin C and malondialdehyde levels in several types of cancer. J. Clin. Pharm. Ther. 20259–263. 10.1111/j.1365-2710.1995.tb00660.x [PubMed] [CrossRef]
  151. Tsukada Y., Fang J., Erdjument-Bromage H., Warren M. E., Borchers C. H., Tempst P., et al. (2006). Histone demethylation by a family of JmjC domain-containing proteins. Nature 439 811–816. 10.1038/nature04433 [PubMed] [CrossRef]
  152. Verrax J., Calderon P. B. (2008). The controversial place of vitamin C in cancer treatment. Biochem. Pharmacol. 76 1644–1652. 10.1016/j.bcp.2008.09.024 [PubMed] [CrossRef]
  153. Verrax J., Calderon P. B. (2009). Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic. Biol. Med. 47 32–40. 10.1016/j.freeradbiomed.2009.02.016 [PubMed] [CrossRef]
  154. Vollbracht C., Schneider B., Leendert V., Weiss G., Auerbach L., Beuth J. (2011). Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany. In Vivo 25 983–990. [PubMed]
  155. Wang C., Lv H., Yang W., Li T., Fang T., Lv G., et al. (2017). SVCT-2 determines the sensitivity to ascorbate-induced cell death in cholangiocarcinoma cell lines and patient derived xenografts. Cancer Lett. 398 1–11. 10.1016/j.canlet.2017.03.039 [PubMed] [CrossRef]
  156. Wang G., Mustafi S., Camarena V., Volmar C. H., Huff T. C., Sant D. W., et al. (2017). Vitamin C sensitizes melanoma to BET inhibitors. Cancer Res. 78 572–583. [PMC free article] [PubMed]
  157. Wang T., Chen K., Zeng X., Yang J., Wu Y., Shi X., et al. (2011). The histone demethylases Jhdm1a/1b enhance somatic cell reprogramming in a vitamin-C-dependent manner. Cell Stem Cell 9575–587. 10.1016/j.stem.2011.10.005 [PubMed] [CrossRef]
  158. Weijl N. I., Hopman G. D., Wipkink-Bakker A., Lentjes E. G., Berger H. M., Cleton F. J., et al. (1998). Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients.Ann. Oncol. 9 1331–1337. 10.1023/A:1008407014084 [PubMed] [CrossRef]
  159. Welsh J. L., Wagner B. A., van’t Erve T. J., Zehr P. S., Berg D. J., Halfdanarson T. R., et al. (2013). Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother. Pharmacol.71 765–775. 10.1007/s00280-013-2070-8 [PMC free article] [PubMed] [CrossRef]
  160. Wilkes J. G., O’Leary B. R., Du J., Klinger A. R., Sibenaller Z. A., Doskey C. M., et al. (2018). Pharmacologic ascorbate (P-AscH(-)) suppresses hypoxia-inducible Factor-1alpha (HIF-1alpha) in pancreatic adenocarcinoma. Clin. Exp. Metastasis. 35 37–51. 10.1007/s10585-018-9876-z[PMC free article] [PubMed] [CrossRef]
  161. Wilson M. K., Baguley B. C., Wall C., Jameson M. B., Findlay M. P. (2014). Review of high-dose intravenous vitamin C as an anticancer agent. Asia Pac. J. Clin. Oncol. 10 22–37. 10.1111/ajco.12173 [PubMed] [CrossRef]
  162. Wohlrab C., Phillips E., Dachs G. U. (2017). Vitamin C transporters in cancer: current understanding and gaps in knowledge. Front. Oncol. 7:74. 10.3389/fonc.2017.00074 [PMC free article] [PubMed] [CrossRef]
  163. Wong K., Thomson C., Bailey R. R., McDiarmid S., Gardner J. (1994). Acute oxalate nephropathy after a massive intravenous dose of vitamin C. Aust. N. Z. J. Med. 24 410–411. 10.1111/j.1445-5994.1994.tb01477.x [PubMed] [CrossRef]
  164. Xia J., Xu H., Zhang X., Allamargot C., Coleman K. L., Nessler R., et al. (2017). Multiple myeloma tumor cells are selectively killed by pharmacologically-dosed ascorbic acid. EBioMedicine 18 41–49. 10.1016/j.ebiom.2017.02.011 [PMC free article] [PubMed] [CrossRef]
  165. Yang G., Yan Y., Ma Y., Yang Y. (2017). Vitamin C at high concentrations induces cytotoxicity in malignant melanoma but promotes tumor growth at low concentrations. Mol. Carcinog. 56 1965–1976. 10.1002/mc.22654 [PubMed] [CrossRef]
  166. Yeom C. H., Jung G. C., Song K. J. (2007). Changes of terminal cancer patients’ health-related quality of life after high dose vitamin C administration. J. Korean Med. Sci. 22 7–11. 10.3346/jkms.2007.22.1.7 [PMC free article] [PubMed] [CrossRef]
  167. Yeom C. H., Lee G., Park J. H., Yu J., Park S., Yi S. Y., et al. (2009). High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis. J. Transl. Med. 7:70. 10.1186/1479-5876-7-70[PMC free article] [PubMed] [CrossRef]
  168. Yin R., Mao S. Q., Zhao B., Chong Z., Yang Y., Zhao C., et al. (2013). Ascorbic acid enhances Tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals. J. Am. Chem. Soc. 135 10396–10403. 10.1021/ja4028346 [PubMed] [CrossRef]
  169. Yun J., Mullarky E., Lu C., Bosch K. N., Kavalier A., Rivera K., et al. (2015). Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350 1391–1396. 10.1126/science.aaa5004 [PMC free article] [PubMed] [CrossRef]
  170. Zhang Z. Z., Lee E. E., Sudderth J., Yue Y., Zia A., Glass D., et al. (2016). Glutathione depletion, pentose phosphate pathway activation, and hemolysis in erythrocytes protecting cancer cells from vitamin C-induced oxidative stress. J. Biol. Chem. 291 22861–22867. 10.1074/jbc.C116.748848[PMC free article] [PubMed] [CrossRef]
  171. Zhao H., Zhu H., Huang J., Zhu Y., Hong M., Zhu H., et al. (2018). The synergy of vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia. Leuk Res. 66 1–7. 10.1016/j.leukres.2017.12.009 [PubMed] [CrossRef]
  172. Shenoy N, Creagan E, Witzig T, Levine M. Ascorbic Acid in Cancer Treatment: Let the Phoenix Fly. Cancer Cell. 2018;34(5):700–706. doi:10.1016/j.ccell.2018.07.014 https://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq