Ascorbate in Cancer Therapy: Comparison
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Jaime González-Montero.

Cancer is a disease of high mortality, and its prevalence has increased steadily in the last few years. Ascorbate (ascorbic acid or vitamin C) is a potent water-soluble antioxidant that is produced in most mammals but is not synthesised endogenously in humans, which lack enzymes for its synthesis. Ascorbate has antioxidant effects that correspond closely to the dose administered. Interestingly, this natural antioxidant induces oxidative stress when given intravenously at a high dose, a paradoxical effect due to its interactions with iron. Importantly, this deleterious property of ascorbate can result in increased cell death. Although, historically, ascorbate has been reported to exhibit anti-tumour properties, this effect has been questioned due to the lack of available mechanistic detail. Recently, new evidence has emerged implicating ferroptosis in several types of oxidative stress-mediated cell death, such as those associated with ischemia–reperfusion. This effect could be positively modulated by the interaction of iron and high ascorbate dosing, particularly in cell systems having a high mitotic index. In addition, it has been reported that ascorbate may behave as an adjuvant of favourable anti-tumour effects in cancer therapies such as radiotherapy, radio-chemotherapy, chemotherapy, immunotherapy, or even in monotherapy, as it facilitates tumour cell death through the generation of reactive oxygen species and ferroptosis.

  • cancer
  • ascorbate
  • oxidative stress
  • ferroptosis
  • iron

1. Introduction

Most applications of ascorbate in human medicine are related to its function in oxidation–reduction reactions. Ascorbate plays a pro-oxidant role by providing electrons to keep prosthetic metal ions in their reduced forms (e.g., cuprous ions in monooxygenases and ferrous ions in dioxygenases) [6][1].
  • Collagen production: Ascorbate plays the role of a coenzyme for prolyl and lysyl hydroxylases in order to convert protocollagen to collagen. Ascorbate is necessary for the maintenance of connective tissue and the wound healing process [7][2].
  • Iron, haemoglobin metabolism, and erythrocyte maturation: Ascorbate enhances iron absorption by keeping it in the ferrous form. Due its reducing property, vitamin C helps the storage form of iron (complexed with ferritin) and its metabolisation [8][3]. Ascorbic acid is also involved in the production of the active form of folic acid and in erythrocyte maturation [9][4].
  • Amino acid metabolism: Ascorbate is essential for tryptophan’s hydroxylation to hydroxytryptophan in the serotonin synthesis [10][5], and for the oxidation of p- hydroxyphenylpyruvate to homogentisic acid in tyrosine metabolism [11][6].
  • Hormone synthesis: The synthesis of many hormones requires vitamin C. Ascorbate is an important cofactor of dopamine β-hydroxylase, the enzyme required to convert dopamine into norepinephrine [12][7]. Ascorbate is also an essential cofactor for the enzyme peptidylglycine α-amidating mono-oxygenase, which is required for the synthesis of vasopressin. Moreover, ascorbate may contribute to the magnitude of vasopressin biosynthesis [13][8]. Ascorbate is necessary for the hydroxylation reactions in the synthesis of corticosteroid hormones [14][9].
  • Immunological function: Ascorbate enhances the synthesis of immunoglobulins and increases the phagocytic action of leucocytes [15][10]. Moreover, vitamin C has been shown to regulate the expression of pro-inflammatory and anti-inflammatory cytokines, to improve chemotaxis and phagocytosis, to enhance lymphocytic proliferation, and to assist in the oxidative neutrophilic killing of bacteria [13][8].
  • Prevention of some diseases: Vitamin C concentrations may be low in acute illnesses, including myocardial infarction, pancreatitis, and sepsis [16][11]. Ascorbate, as an antioxidant, reduces coronary heart diseases and the risk of cancer [17][12]. Ascorbate has been shown to be involved in other biochemical activities [18][13], protecting the body from free radicals, enhancing the absorption of iron from vegetables, cereals, and fruits, helping in resistance against the common cold, and preventing some types of cancer [19][14].
  • Ascorbate is widely known for its immunological functions. Ascorbate enhances the synthesis of immunoglobulins and increases the phagocytic action of leucocytes [15][10]. Moreover, vitamin C has been shown to regulate the expression of pro-inflammatory and anti-inflammatory cytokines, to improve chemotaxis and phagocytosis, to enhance lymphocytic proliferation, and to assist in the oxidative neutrophilic killing of bacteria [13][8]. More broadly, low levels of vitamin C have been implicated in a variety of acute illnesses, suggesting a potential application in disease prevention. Low levels of vitamin C have been described in association with acute myocardial infarction, pancreatitis, and sepsis [16][11]. Ascorbate, as an antioxidant, reduces coronary heart diseases and the risk of developing cancer [17][12]. Its myriad biochemical activities [18][13] have been proposed to contribute to a variety of health benefits, including protecting the body from free radicals, enhancing the absorption of iron from vegetables, cereals, and fruits, contributing to resistance against the common cold [19][14].

2. Application of Ascorbate in Cancer Therapy

The role of ascorbate has been studied in both animal and in vitro models, both for its cytotoxic effect as a monotherapy treatment and as an adjuvant to oncologic therapies. Ascorbate been shown to have a cytotoxic effect in a colorectal cancer cell line, where its effect is dependent on the expression of sodium-dependent vitamin C transporter 2 (SVCT-2) [27,73][15][16]. In gastric cancer cell lines, the sensitivity of cells to the cytotoxic effect of ascorbate was inversely correlated with GLUT-1 expression, suggesting GLUT-1 expression as a biomarker predicting sensitivity to ascorbate therapy [75][17]. Direct cytotoxic effects of ascorbate were also demonstrated in a murine model of melanoma [76][18]. As an adjuvant to conventional chemotherapy treatments, ascorbate has been shown in non-small-cell lung cancer cell lines to enhance the cytotoxicity of chemotherapy [77,78][19][20]. In pancreatic cancer cell lines, ascorbate enhances the cytotoxic effect of gemcitabine and paclitaxel by decreasing chemoresistance [79][21]. In a study that included in vitro experiments with 11 different cancer cell lines, around half of the cell lines tested were resistant to ascorbate cytotoxicity, a response associated with high levels of catalase activity [80][22], suggesting a potential role for catalase in mediating ascorbate’s cytotoxicity effects. Finally, both cell lines and a murine xenograft model of colorectal cancer with KRAS mutation demonstrated that high concentrations of ascorbate enhanced the cytotoxic effect of chemotherapy [81][23]. In parallel, in preclinical models of KRAS-mutated colorectal cancer, the combination of ascorbate and chemotherapy improved tumour regression, and this response depended on SVCT-2 expression in tumour cells [82][24]. More recently, ascorbate has also been powerfully combined with biological therapy in cancer treatment. In HER2-positive breast cancer cell lines, treatment with high concentrations of ascorbate and a monoclonal antibody targeting HER2, trastuzumab, resulted in a decrease in tumour cell proliferation compared to trastuzumab alone [83][25]. Furthermore, a combination of a high concentration of ascorbate and immunotherapy (anti PD1 and/or anti CTLA4 antibodies) showed improved cytotoxic effects in pancreatic, breast, melanoma, and colorectal cancer models [84][26]. These promising results suggest that ascorbate enhances cytotoxic tumour cell killing in immunotherapy. Further studies addressing the mechanisms of this phenomenon will make clear whether this synergy will be clinically relevant. Overall, observational prospective cohort studies have found no association or a modest inverse association between ascorbate intake and the risk of cancer [97,98,99,100][27][28][29][30]. In breast cancer, two large prospective studies found that dietary intake of ascorbate is inversely associated with breast cancer incidence in certain subgroups. In one study (the Nurses’ Health Study), premenopausal women with a family history of breast cancer who consumed an average of 205 mg/day of ascorbate from food had a lower risk of breast cancer than those who consumed an average of 70 mg/day [101][31]. In a second study (referred to as the Swedish Mammography Cohort), overweight women who consumed an average of 110 mg/day of ascorbate had a lower risk of breast cancer compared with overweight women who consumed an average of 31 mg/day [102][32]. More recent prospective cohort studies reported no association between dietary or supplemental ascorbate oral intake and breast cancer [103,104][33][34]. Ascorbate has been used to promote damage to cancer cells in radiotherapy and chemotherapy through oxidative stress generation. Ascorbate has been shown to have cytotoxic effects as a therapy adjuvant to chemoradiation in the treatment of oesophageal cancer [116][35] and gastric cancer [117][36], non-small-cell lung cancer and glioblastoma [78][20], and pancreatic cancer [118,119][37][38]. In addition, intravenous ascorbate has been found to mitigate damage to normal tissue following chemoradiation therapy [91[39][40],120], and it may also have synergistic effects with palliative radiotherapy in patients with bone metastases [121][41]. The effect of ascorbate has been proven as an adjuvant therapy to chemotherapy, as well. Several studies, including case reports and clinical trials, have studied the effect of IV ascorbate in patients with different types of cancer. Two initial reports showed that high-dose IV ascorbate treatment is well tolerated in cancer patients [122,123][42][43]. However, one study with only three cases showed long survival times of patients [123][43], while the second study, reporting 24 cases, failed to detect any anti-cancer activity of ascorbate [122][42]. In a study with 60 patients with different types of cancer, IV ascorbate improved quality of life [124][44]. Ascorbate administrated alone also improved quality of life in a study including 17 patients with different solid tumours, although no patient showed an objective anti-tumour response [110][45]. Two additional studies evaluated the effect of IV ascorbate on the survival of patients with stage IV pancreatic cancer receiving standard chemotherapy treatment. Both studies reported a reduction in tumour mass and improvements in overall survival [111,112][46][47].


  1. Du, J.; Cullen, J.J.; Buettner, G.R. Ascorbic acid: Chemistry, biology and the treatment of cancer. Biochim. Biophys. Acta 2012, 1826, 443–457.
  2. Murad, S.; Grove, D.; Lindberg, K.A.; Reynolds, G.; Sivarajah, A.; Pinnell, S.R. Regulation of collagen synthesis by ascorbic acid. Proc. Natl. Acad. Sci. USA 1981, 78, 2879–2882.
  3. Lane, D.J.; Richardson, D.R. The active role of vitamin C in mammalian iron metabolism: Much more than just enhanced iron absorption! Free Radic. Biol. Med. 2014, 75, 69–83.
  4. Magana, A.A.; Reed, R.L.; Koluda, R.; Miranda, C.L.; Maier, C.S.; Stevens, J.F. Vitamin C Activates the Folate-Mediated One-Carbon Cycle in C2C12 Myoblasts. Antioxidants 2020, 9, 217.
  5. Cooper, J.R. The role of ascorbic acid in the oxidation of tryptophan to 5-hydroxytryptophan. Ann. N. Y. Acad. Sci. 1961, 92, 208–211.
  6. Doseděl, M.; Jirkovský, E.; Macáková, K.; Krčmová, L.K.; Javorská, L.; Pourová, J.; Mercolini, L.; Remião, F.; Nováková, L.; Mladěnka, P. Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination. Nutrients 2021, 13, 615.
  7. May, J.M.; Qu, Z.C.; Meredith, M.E. Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. Biochem. Biophys. Res. Commun. 2012, 426, 148–152.
  8. Gordon, D.S.; Rudinsky, A.J.; Guillaumin, J.; Parker, V.J.; Creighton, K.J. Vitamin C in Health and Disease: A Companion Animal Focus. Top. Companion Anim. Med. 2020, 39, 100432.
  9. Mitani, F.; Ogishima, T.; Mukai, K.; Suematsu, M. Ascorbate stimulates monooxygenase-dependent steroidogenesis in adrenal zona glomerulosa. Biochem. Biophys. Res. Commun. 2005, 338, 483–490.
  10. Carr, A.C.; Maggini, S. Vitamin C and Immune Function. Nutrients 2017, 9, 1211.
  11. Kashiouris, M.G.; L’Heureux, M.; Cable, C.A.; Fisher, B.J.; Leichtle, S.W.; Fowler, A.A. The Emerging Role of Vitamin C as a Treatment for Sepsis. Nutrients 2020, 12, 292.
  12. Morelli, M.B.; Gambardella, J.; Castellanos, V.; Trimarco, V.; Santulli, G. Vitamin C and Cardiovascular Disease: An Update. Antioxidants 2020, 9, 1227.
  13. Chambial, S.; Dwivedi, S.; Shukla, K.K.; John, P.J.; Sharma, P.; Vitamin, C. in disease prevention and cure: An overview. Indian J. Clin. Biochem. 2013, 28, 314–328.
  14. Pawlowska, E.; Szczepanska, J.; Blasiak, J. Pro- and Antioxidant Effects of Vitamin C in Cancer in correspondence to Its Dietary and Pharmacological Concentrations. Oxid. Med. Cell. Longev. 2019, 2019, 7286737.
  15. Tóth, S.Z.; Lőrincz, T.; Szarka, A. Concentration Does Matter: The Beneficial and Potentially Harmful Effects of Ascorbate in Humans and Plants. Antioxid. Redox Signal. 2018, 29, 1516–1533.
  16. Cho, S.; Chae, J.S.; Shin, H.; Shin, Y.; Song, H.; Kim, Y.; Yoo, B.C.; Roh, K.; Cho, S.; Kil, E.J.; et al. Hormetic dose response to L-ascorbic acid as an anti-cancer drug in colorectal cancer cell lines according to SVCT-2 expression. Sci. Rep. 2018, 8, 11372.
  17. Corti, A.; Belcastro, E.; Pompella, A. Antitumoral effects of pharmacological ascorbate on gastric cancer cells: GLUT1 expression may not tell the whole story. Theranostics 2018, 8, 6035–6037.
  18. Nakanishi, K.; Hiramoto, K.; Sato, E.F.; Ooi, K. High-Dose Vitamin C Administration Inhibits the Invasion and Proliferation of Melanoma Cells in Mice Ovary. Biol. Pharm. Bull. 2021, 44, 75–81.
  19. Chiang, C.D.; Song, E.J.; Yang, V.C.; Chao, C.C. Ascorbic acid increases drug accumulation and reverses vincristine resistance of human non-small-cell lung-cancer cells. Biochem. J. 1994, 301 Pt 3, 759–764.
  20. Schoenfeld, J.D.; Sibenaller, Z.A.; Mapuskar, K.A.; Wagner, B.A.; Cramer-Morales, K.L.; Furqan, M.; Sandhu, S.; Carlisle, T.L.; Smith, M.C.; Abu Hejleh, T.; 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 2017, 31, 487–500.e8, Erratum in: Cancer Cell 2017, 32, 268.
  21. O’Leary, B.R.; Alexander, M.S.; Du, J.; Moose, D.L.; Henry, M.D.; Cullen, J.J. Pharmacological ascorbate inhibits pancreatic cancer metastases via a peroxide-mediated mechanism. Sci. Rep. 2020, 10, 17649.
  22. Erudaitius, D.; Mantooth, J.; Huang, A.; Soliman, J.; Doskey, C.M.; Buettner, G.R.; Rodgers, V.G.J. Calculated cell-specific intracellular hydrogen peroxide concentration: Relevance in cancer cell susceptibility during ascorbate therapy. Free Radic. Biol. Med. 2018, 120, 356–367.
  23. Aguilera, O.; Muñoz-Sagastibelza, M.; Torrejón, B.; Borrero-Palacios, A.; Del Puerto-Nevado, L.; Martínez-Useros, J.; Rodriguez-Remirez, M.; Zazo, S.; García, E.; Fraga, M.; et al. Vitamin C uncouples the Warburg metabolic switch in KRAS mutant colon cancer. Oncotarget 2016, 7, 47954–47965.
  24. Jung, S.A.; Lee, D.H.; Moon, J.H.; Hong, S.W.; Shin, J.S.; Hwang, I.Y.; Shin, Y.J.; Kim, J.H.; Gong, E.Y.; Kim, S.M.; et al. L-Ascorbic acid can abrogate SVCT-2-dependent cetuximab resistance mediated by mutant KRAS in human colon cancer cells. Free Radic. Biol. Med. 2016, 95, 200–208, Erratum in: Free Radic. Biol. Med. 2016, 97, 620.
  25. Lee, S.J.; Jeong, J.H.; Lee, I.H.; Lee, J.; Jung, J.H.; Park, H.Y.; Lee, D.H.; Chae, Y.S. Effect of High-dose Vitamin C Combined With Anti-cancer Treatment on Breast Cancer Cells. Anticancer Res. 2019, 39, 751–758.
  26. Magrì, A.; Germano, G.; Lorenzato, A.; Lamba, S.; Chilà, R.; Montone, M.; Amodio, V.; Ceruti, T.; Sassi, F.; Arena, S.; et al. High-dose vitamin C enhances cancer immunotherapy. Sci. Transl. Med. 2020, 12, eaay8707.
  27. Carr, A.C.; Frei, B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am. J. Clin. Nutr. 1999, 69, 1086–1107.
  28. Bertoia, M.; Albanes, D.; Mayne, S.T.; Mannisto, S.; Virtamo, J.; Wright, M.E. No association between fruit, vegetables, antioxidant nutrients and risk of renal cell carcinoma. Int. J. Cancer 2010, 126, 1504–1512.
  29. Heinen, M.M.; Verhage, B.A.; Goldbohm, R.A.; van den Brandt, P.A. Intake of vegetables, fruits, carotenoids and vitamins C and E and pancreatic cancer risk in The Netherlands Cohort Study. Int. J. Cancer 2012, 130, 147–158.
  30. Goodman, M.; Bostick, R.M.; Kucuk, O.; Jones, D.P. Clinical trials of antioxidants as cancer prevention agents: Past, present, and future. Free Radic. Biol. Med. 2011, 51, 1068–1084.
  31. Zhang, S.; Hunter, D.J.; Forman, M.R.; Rosner, B.A.; Speizer, F.E.; Colditz, G.; Manson, J.E.; Hankinson, S.E.; Willett, W.C. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J. Natl. Cancer Inst. 1999, 91, 547–556.
  32. Michels, K.B.; Holmberg, L.; Bergkvist, L.; Ljung, H.; Bruce, A.; Wolk, A. Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women. Int. J. Cancer 2001, 91, 563–567.
  33. Hutchinson, J.; Lentjes, M.A.; Greenwood, D.C.; Burley, V.J.; E Cade, J.; Cleghorn, C.L.; E Threapleton, D.; Key, T.J.; Cairns, B.J.; Keogh, R.H.; et al. Vitamin C intake from diary recordings and risk of breast cancer in the UK Dietary Cohort Consortium. Eur. J. Clin. Nutr. 2012, 66, 561–568.
  34. Nagel, G.; Linseisen, J.; van Gils, C.H.; Peeters, P.H.; Boutron-Ruault, M.C.; Clavel-Chapelon, F.; Romieu, I.; Tjonneland, A.; Olsen, A.; Roswall, N.; et al. Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Breast Cancer Res. Treat. 2010, 119, 753–765.
  35. Abdel-Latif, M.M.M.; Babar, M.; Kelleher, D.; Reynolds, J.V. A pilot study of the impact of Vitamin C supplementation with neoadjuvant chemoradiation on regulators of inflammation and carcinogenesis in esophageal cancer patients. J. Cancer Res. Ther. 2019, 15, 185–191.
  36. O’Leary, B.R.; Houwen, F.K.; Johnson, C.L.; Allen, B.G.; Mezhir, J.J.; Berg, D.J.; Cullen, J.J.; Spitz, D.R. Pharmacological Ascorbate as an Adjuvant for Enhancing Radiation-Chemotherapy Responses in Gastric Adenocarcinoma. Radiat. Res. 2018, 189, 456–465.
  37. Cieslak, J.A.; Sibenaller, Z.A.; Walsh, S.A.; Ponto, L.L.; Du, J.; Sunderland, J.J.; Cullen, J.J. Fluorine-18-Labeled Thymidine Positron Emission Tomography (FLT-PET) as an Index of Cell Proliferation after Pharmacological Ascorbate-Based Therapy. Radiat. Res. 2016, 185, 31–38.
  38. Du, J.; Cieslak, J.A., 3rd; Welsh, J.L.; Sibenaller, Z.A.; Allen, B.G.; Wagner, B.A.; Kalen, A.L.; Doskey, C.M.; Strother, R.K.; Button, A.M.; et al. Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer. Cancer Res. 2015, 75, 3314–3326.
  39. Alexander, M.S.; Wilkes, J.G.; Schroeder, S.R.; Buettner, G.R.; Wagner, B.A.; Du, J.; Gibson-Corley, K.; O’Leary, B.R.; Spitz, D.R.; Buatti, J.M.; et al. Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer. Cancer Res. 2018, 78, 6838–6851.
  40. Haskins, A.H.; Buglewicz, D.J.; Hirakawa, H.; Fujimori, A.; Aizawa, Y.; Kato, T.A. Palmitoyl ascorbic acid 2-glucoside has the potential to protect mammalian cells from high-LET carbon-ion radiation. Sci. Rep. 2018, 8, 13822.
  41. Günes-Bayir, A.; Kiziltan, H.S. Palliative Vitamin C Application in Patients with Radiotherapy-Resistant Bone Metastases: A Retrospective Study. Nutr. Cancer 2015, 67, 921–925.
  42. Hoffer, L.J.; Levine, M.; Assouline, S.; Melnychuk, D.; Padayatty, S.J.; Rosadiuk, K.; Rousseau, C.; Robitaille, L.; Miller, W.H., Jr. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. 2008, 19, 1969–1974, Erratum in: Ann. Oncol. 2008, 19, 2095.
  43. Padayatty, S.J.; Riordan, H.D.; Hewitt, S.M.; Katz, A.; Hoffer, L.J.; Levine, M. Intravenously administered vitamin C as cancer therapy: Three cases. CMAJ 2006, 174, 937–942.
  44. Takahashi, H.; Mizuno, H.; Yanagisawa, A. High-dose intravenous vitamin C improves quality of life in cancer patients. Personal. Med. Univ. 2012, 1, 49–53.
  45. Stephenson, C.M.; Levin, R.D.; Spector, T.; Lis, C.G. 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. 2013, 72, 139–146.
  46. Welsh, J.L.; Wagner, B.A.; van’t Erve, T.J.; Zehr, P.S.; Berg, D.J.; Halfdanarson, T.R.; Yee, N.S.; Bodeker, K.L.; Du, J.; Roberts, L.J., 2nd; et al. 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. 2013, 71, 765–775.
  47. Monti, D.A.; Mitchell, E.; Bazzan, A.J.; Littman, S.; Zabrecky, G.; Yeo, C.J.; Pillai, M.V.; Newberg, A.; Deshmukh, S.; Levine, M. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS ONE 2012, 7, e29794.
Video Production Service