Effect of Vitamin C on Cancer Process

Year 2024, Volume: 44 Issue: 3, 253 - 262, 01.09.2024

Omnia Abdo Mahmoud Hemdan , Gözde Girgin , Terken Baydar

https://doi.org/10.52794/hujpharm.1484625

Abstract

The diverse roles of vitamin C in combatting cancer through its antioxidative and pro-oxidative properties, as well as its immune-boosting functions, are significant. Vitamin C acts as a cofactor for oxygenase enzymes containing iron or copper, aiding in two key processes: firstly, the stimulation of reactive oxygen species production, which selectively targets cancer cells, and secondly, the regulation of cellular metabolism and epigenetic processes involving DNA and histone demethylases, thereby diminishing tumorigenesis. Although various studies highlight the potential effectiveness of vitamin C against different cancer types in laboratory and animal studies, both as a standalone treatment and in combination with traditional chemotherapy and radiation, its role in clinical or non-clinical human studies remains unclear and contentious. Recent papers of randomized clinical trials or observational studies have not yielded conclusive evidence supporting vitamin C’s clinical efficacy in cancer treatment or prevention. In this review, vitamin C usage and its efficacy in cancer therapy approaches have been focused and discussed. In conclusion, it may be speculated that these complexities highlight the need for larger, high-quality randomized clinical trials to provide more definitive understanding of vitamin C’s anticancer potential and to establish appropriate clinical recommendations.

Keywords

Vitamin C, Ascorbic acid, Cancer, Cancer therapy, Supplementation

Ethical Statement

Not necessary.

Supporting Institution

None

Project Number

None

Thanks

None

Kanser sürecinde vitamin C'nin etkisi

Abstract

The diverse roles of vitamin C in combatting cancer through its antioxidative and pro-oxidative properties, as well as its immune-boosting functions, are significant. Vitamin C acts as a cofactor for oxygenase enzymes containing iron or copper, aiding in two key processes: firstly, the stimulation of reactive oxygen species production, which selectively targets cancer cells, and secondly, the regulation of cellular metabolism and epigenetic processes involving DNA and histone demethylases, thereby diminishing tumorigenesis. Although various studies highlight the potential effectiveness of vitamin C against different cancer types in laboratory and animal studies, both as a standalone treatment and in combination with traditional chemotherapy and radiation, its role in clinical or non-clinical human studies remains unclear and contentious. Recent papers of randomized clinical trials or observational studies have not yielded conclusive evidence supporting vitamin C's clinical efficacy in cancer treatment or prevention. In this review, vitamin C usage in cancer therapy and its efficacy in cancer therapy approaches have been focused and discussed. In conclusion, it may be speculated that these complexities highlight the need for larger, high-quality randomized clinical trials to provide more definitive understanding of vitamin C's anticancer potential and to establish appropriate clinical recommendations.

Keywords

Vitamin C, Askorbik asit, Destek, Kanser tedavisi

Ethical Statement

Gerekli değil.

Supporting Institution

None.

Project Number

None

Thanks

None.

References

• 1. Iqbal, K., Khan, A., & Khattak, M., M., A., K. (2003). Biological Significance of Ascorbic Acid (Vitamin C) in Human Health - A Review. Pak J Nutr. 3(1), 5–13. https://doi. org/10.3923/PJN.2004.5.13
• 2. Carr, A. C., & Lykkesfeldt, J. (2021). Discrepancies in global vitamin C recommendations: a review of RDA criteria and underlying health perspectives. Crit Rev Food Sci Nutr. 61(5), 742–755. https://doi.org/10.1080/10408398.2020.1744513
• 3. Levine, M., Conry-Cantilena, C., Wang, Y., Welch, R. W., Washko, P. W., Dhariwal, K. R., Park, J. B., Lazarev, A., Graumlich, J. F., King, J., & Cantilena, L. R. (1996). Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc Natl Acad Sci. 93(8), 3704– 3709. https://doi.org/10.1073/PNAS.93.8.3704
• 4. Du, J., Cullen, J. J., & Buettner, G. R. (2012). Ascorbic acid: Chemistry, biology and the treatment of cancer. Biochim Biophys Acta Rev Cancer. 1826(2), 443–457. https://doi. org/10.1016/J.BBCAN.2012.06.003
• 5. Hulse, J. D., Ellis, S. R., & Henderson, L. M. (1978). Carnitine biosynthesis. beta-Hydroxylation of trimethyllysine by an alpha- ketoglutarate-dependent mitochondrial dioxygenase. J Biol Chem. 253(5), 1654–1659. https://doi.org/10.1016/S0021- 9258(17)34915-3
• 6. Vissers, M. C. M., Kuiper, C., & Dachs, G. U. (2014). Regulation of the 2-oxoglutarate-dependent dioxygenases and implications for cancer. Biochem Soc Trans. 42(4), 945–951. https://doi.org/10.1042/BST20140118
• 7. Kontoghiorghes, G. J., Kolnagou, A., Kontoghiorghe, C. N., Mourouzidis, L., Timoshnikov, V. A., & Polyakov, N. E. (2020). Trying to Solve the Puzzle of the Interaction of Ascorbic Acid and Iron: Redox, Chelation and Therapeutic Implications. Medicines. 2020, Vol. 7, Page 45, 7(8), 45. https://doi. org/10.3390/MEDICINES7080045
• 8. Teucher, B., Olivares, M., & Cori, H. (2004). Enhancers of Iron Absorption: Ascorbic Acid and other Organic Acids. Int J Vitam Nutr Res. 74(6), 403–419. https://doi.org/10.1024/0300- 9831.74.6.403
• 9. Mayland, C. R., Bennett, M. I., & Allan, K. (2005). Vitamin C deficiency in cancer patients. Palliat Med. 19(1), 17–20. https://doi.org/10.1191/0269216305PM970OA
• 10. Huijskens, M. J. A. J., Wodzig, W. K. W. H., Walczak, M., Germeraad, W. T. V., & Bos, G. M. J. (2016). Ascorbic acid serum levels are reduced in patients with hematological malignancies. Results Immunol. 6, 8–10. https://doi.org/10.1016/J. RINIM.2016.01.001
• 11. Chambial, S., Dwivedi, S., Shukla, K. K., John, P. J., & Sharma, P. (2013). Vitamin C in disease prevention and cure: An overview. Indian J Clin Biochem. 28(4), 314–328. https://doi. org/10.1007/S12291-013-0375-3
• 12. Ströhle, A., Wolters, M., & Hahn, A. (2011). Micronutrients at the interface between inflammation and infection - ascorbic acid and calciferol. part 1: General overview with a focus on ascorbic acid. Inflamm Allergy Drug Targets. 10(1), 54–63. https://doi.org/10.2174/187152811794352105
• 13. Ang, A., Pullar, J. M., Currie, M. J., & Vissers, M. C. M. (2018). Vitamin C and immune cell function in inflammation and cancer. Biochem Soc Trans. 46(5), 1147–1159. https://doi. org/10.1042/BST20180169
• 14. Agathocleous, M., Meacham, C. E., Burgess, R. J., Piskounova, E., Zhao, Z., Crane, G. M., Cowin, B. L., Bruner, E., Murphy, M. M., Chen, W., Spangrude, G. J., Hu, Z., DeBerardinis, R. J., & Morrison, S. J. (2017). Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 2017 549:7673, 549 (7673), 476–481. https://doi.org/10.1038/ nature23876
• 15. Henke, N., Ferreirós, N., Geisslinger, G., Ding, M. G., Essler, S., Fuhrmann, D. C., Geis, T., Namgaladze, D., Dehne, N., Brüne, B., Henke, N., Ferreirós, N., Geisslinger, G., Ding, M. G., Essler, S., Fuhrmann, D. C., Geis, T., Namgaladze, D., Dehne, N., & Brüne, B. (2016). Loss of HIF-1β in macrophages attenuates AhR/ARNT-mediated tumorigenesis in a PAH-driven tumor model. Oncotarget. 7(18), 25915–25929. https://doi.org/10.18632/ONCOTARGET.8297
• 16. Mastrangelo, D., Pelosi, E., Castelli, G., Lo-Coco, F., & Testa, U. (2018a). Mechanisms of anti-cancer effects of ascorbate: Cytotoxic activity and epigenetic modulation. Blood Cells Mol Dis. 69, 57–64. https://doi.org/10.1016/J.BCMD.2017.09.005
• 17. Mingay, M., Chaturvedi, A., Bilenky, M., Cao, Q., Jackson, L., Hui, T., Moksa, M., Heravi-Moussavi, A., Humphries, R. K., Heuser, M., & Hirst, M. (2017). Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia. Leukemia 2018 32:1, 32(1), 11–20. https://doi.org/10.1038/ leu.2017.171
• 18. Cull, A. H., Snetsinger, B., Buckstein, R., Wells, R. A., & Rauh, M. J. (2017). Tet2 restrains inflammatory gene expression in macrophages. Exp Hematol. 55, 56-70. e13. https://doi. org/10.1016/J.EXPHEM.2017.08.001
• 19. Buettner, G. R. (1993). The Pecking Order of Free Radicals and Antioxidants: Lipid Peroxidation, α-Tocopherol, and Ascorbate. Arch Biochem Biophys. 300(2), 535–543. https://doi. org/10.1006/ABBI.1993.1074
• 20. Riley, P. A. (1994). Free Radicals in Biology: Oxidative Stress and the Effects of Ionizing Radiation. Int J Radiat Biol. 65(1), 27–33. https://doi.org/10.1080/09553009414550041
• 21. Asada, K. (1999). The Water-Water Cycle In Chloroplasts: Scavenging of Active Oxygens and Dissipation of Excess Photons. Annu Rev Plant Physiol Plant Mol Biol. 50, 601– 639. https://doi.org/10.1146/ANNUREV.ARPLANT.50.1.601
• 22. Smirnoff, N. (2000). Ascorbic acid: metabolism and functions of a multi-facetted molecule. Curr Opin Plant Biol. 3(3), 229- 235. https://pubmed.ncbi.nlm.nih.gov/10837263/
• 23. 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(2), 249–253. https://doi.org/10.1016/J. BBRC.2010.02.012
• 24. Yin, X., Chen, K., Cheng, H., Chen, X., Feng, S., Song, Y., & Liang, L. (2022). Chemical Stability of Ascorbic Acid Integrated into Commercial Products: A Review on Bioactivity and Delivery Technology. Antioxidants. 2022, Vol. 11, Page 153, 11(1), 153. https://doi.org/10.3390/ANTIOX11010153
• 25. Ngo, B., Van Riper, J. M., Cantley, L. C., & Yun, J. (2019). Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer. 2019 19:5, 19(5), 271–282. https://doi. org/10.1038/s41568-019-0135-7
• 26. Vissers, M. C. M., & Das, A. B. (2018). Potential mechanisms of action for vitamin C in cancer: Reviewing the evidence. Front Physiol. 9 (JUL), 384131. https://doi.org/10.3389/ FPHYS.2018.00809
• 27. Barbosa, A. M., & Martel, F. (2020). Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds. Cancers. 2020, Vol. 12, Page 154, 12(1), 154. https://doi.org/10.3390/CANCERS12010154
• 28. Wilkes, J. G., O’Leary, B. R., Du, J., Klinger, A. R., Sibenaller, Z. A., Doskey, C. M., Gibson-Corley, K. N., Alexander, M. S., Tsai, S., Buettner, G. R., & Cullen, J. J. (2018). Pharmacologic ascorbate (P-AscH−) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma. Clin Exp Metastasis. 35 (1–2), 37–51. https://doi.org/10.1007/S10585-018-9876-Z/ FIGURES/7
• 29. Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, I. I. C., Giannopoulou, E. G., Rago, C., Muley, A., Asara, J. M., Paik, J., Elemento, O., Chen, Z., Pappin, D. J., Dow, L. E., Papadopoulos, N., Gross, S. S., & Cantley, L. C. (2015). Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 350(6266), 1391–1396. https://doi.org/10.1126/SCIENCE. AAA5004
• 30. Pawlowska, E., Szczepanska, J., & Blasiak, J. (2019). Pro- And antioxidant effects of Vitamin C in cancer in correspondence to its dietary and pharmacological concentrations. Oxid Med Cell Longev. 2019. https://doi.org/10.1155/2019/7286737
• 31. Baylin, S. B., & Jones, P. A. (2011). A decade of exploring the cancer epigenome — biological and translational implications. Nat Rev Cancer. 2011 11:10, 11(10), 726–734. https:// doi.org/10.1038/nrc3130
• 32. Shenoy, N., Bhagat, T., Nieves, E., Stenson, M., Lawson, J., Choudhary, G. S., Habermann, T., Nowakowski, G., Singh, R., Wu, X., Verma, A., & Witzig, T. E. (2017). Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. Blood Cancer J. 2017 7:7, 7(7), e587– e587. https://doi.org/10.1038/bcj.2017.65
• 33. Young, J. I., Züchner, S., & Wang, G. (2015). Regulation of the Epigenome by Vitamin C. Annu Rev Nutr. 35(1), 545–564. https://doi.org/10.1146/ANNUREV-NUTR-071714-034228
• 34. Cimmino, L., Dolgalev, I., Wang, Y., Yoshimi, A., Martin, G. H., Wang, J., Ng, V., Xia, B., Witkowski, M. T., Mitchell- Flack, M., Grillo, I., Bakogianni, S., Ndiaye-Lobry, D., Martín, M. T., Guillamot, M., Banh, R. S., Xu, M., Figueroa, M. E., Dickins, R. A., Aifantis, I. (2017). Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell. 170(6), 1079-1095.e20. https://doi.org/10.1016/J. CELL.2017.07.032
• 35. Pavlovic, V., Ciric, M., Petkovic, M., & Golubovic, M. (2023). Vitamin C and epigenetics: A short physiological overview. Open Med. 18(1). https://doi.org/10.1515/MED-2023-0688
• 36. Ravasco, P. (2019). Nutrition in Cancer Patients. J Clin Med. 2019, Vol. 8, Page 1211, 8(8), 1211. https://doi.org/10.3390/ JCM8081211
• 37. Greenwald, P., Clifford, C. K., & Milner, J. A. (2001). Diet and Cancer Prevention. European Eur J Cancer. 37(8), 948–965. https://doi.org/10.1016/S0959-8049(01)00070-3
• 38. Xu, K., Peng, R., Zou, Y., Jiang, X., Sun, Q., & Song, C. (2022). Vitamin C intake and multiple health outcomes: an umbrella review of systematic reviews and meta-analyses. Int J Food Sci Nutr. 73(5), 588–599. https://doi.org/10.1080/0963 7486.2022.2048359
• 39. Chen, Z., Huang, Y., Cao, D., Qiu, S., Chen, B., Li, J., Bao, Y., Wei, Q., Han, P., & Liu, L. (2022). Vitamin C Intake and Cancers: An Umbrella Review. Front Nutr. 8, 812394. https:// doi.org/10.3389/FNUT.2021.812394
• 40. Fu, Y., Xu, F., Jiang, L., Miao, Z., Liang, X., Yang, J., Larsson, S. C., & Zheng, J. S. (2021). Circulating vitamin C concentration and risk of cancers: a Mendelian randomization study. BMC Med. 19(1), 1–14. https://doi.org/10.1186/S12916-021- 02041-1/FIGURES/5
• 41. Yin, L., Yan, H., Chen, K., Ji, Z., Zhang, X., Ji, G., & Zhang, B. (2022). Diet-Derived Circulating Antioxidants and Risk of Digestive System Tumors: A Mendelian Randomization Study. Nutrients. 14(16), 3274. https://doi.org/10.3390/ NU14163274/S1
• 42. Zhao, H., & Jin, X. (2022). Causal associations between dietary antioxidant vitamin intake and lung cancer: A Mendelian randomization study. Front Nutr. 9, 965911. https://doi. org/10.3389/FNUT.2022.965911
• 43. Larsson, S. C., Mason, A. M., Vithayathil, M., Carter, P., Kar, S., Zheng, J. S., & Burgess, S. (2022). Circulating vitamin C and digestive system cancers: Mendelian randomization study. Clin Nutr. 41(9), 2031–2035. https://doi.org/10.1016/J. CLNU.2022.07.040
• 44. Abdel-Latif, M., Babar, M., Kelleher, D., & Reynolds, J. (2019). 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 Cell Ther. 15(1), 185–191. https://doi.org/10.4103/ JCRT.JCRT_763_16
• 45. Furqan, M., Abu-Hejleh, T., Stephens, L. M., Hartwig, S. M., Mott, S. L., Pulliam, C. F., Petronek, M., Henrich, J. B., Fath, M. A., Houtman, J. C., Varga, S. M., Bodeker, K. L., Bossler, A. D., Bellizzi, A. M., Zhang, J., Monga, V., Mani, H., Ivanovic, M., Smith, B. J., Allen, B. G. (2022). Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer. Redox Biol. 53, 102318. https://doi.org/10.1016/J.REDOX.2022.102318
• 46. Hoppe, C., Freuding, M., Büntzel, J., Münstedt, K., & Hübner, J. (2021). Clinical efficacy and safety of oral and intravenous vitamin C use in patients with malignant diseases. J Cancer Res Clin Oncol. 147(10), 3025–3042. https://doi.org/10.1007/ S00432-021-03759-4/FIGURES/2
• 47. 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(4), 285–315. https://doi.org/10.1016/0009-2797(74)90019- 2
• 48. Cameron, E., Campbell, A., & Jack, T. (1975). The orthomolecular treatment of cancer: III. Reticulum cell sarcoma: Double complete regression induced by high-dose ascorbic acid therapy. Chem Biol Interact. 11(5), 387–393. https://doi. org/10.1016/0009-2797(75)90007-1
• 49. 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(10), 3685–3689. https://doi.org/10.1073/PNAS.73.10.3685
• 50. Carr, A. C. (2019). Vitamin C administration in the critically ill: A summary of recent meta-analyses. Crit Care. 23(1), 1–3. https://doi.org/10.1186/S13054-019-2538-Y/TABLES/1
• 51. Levine, M., Padayatty, S. J., & Espey, M. G. (2011). Vitamin C: A Concentration-Function Approach Yields Pharmacology and Therapeutic Discoveries. Adv Nutr. 2(2), 78–88. https:// doi.org/10.3945/AN.110.000109
• 52. Rasmussen, K. D., & Helin, K. (2016). Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 30(7), 733–750. https://doi.org/10.1101/GAD.276568.115
• 53. van Gorkom, G. N. Y., Lookermans, E. L., Van Elssen, C. H. M. J., & Bos, G. M. J. (2019). The Effect of Vitamin C (Ascorbic Acid) in the Treatment of Patients with Cancer: A Systematic Review. Nutrients. 2019, Vol. 11, Page 977, 11(5), 977. https://doi.org/10.3390/NU11050977
• 54. Wang, F., He, M. M., Xiao, J., Zhang, Y. Q., Yuan, X. L., Fang, W. J., Zhang, Y., Wang, W., Hu, X. H., Ma, Z. G., Yao, Y. C., Zhuang, Z. X., Zhou, F. X., Ying, J. E., Yuan, Y., Zou, Q. F., Guo, Z. Q., Wu, X. Y., Jin, Y., Xu, R. H. (2022). A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study). Clin Cancer Res.28(19), 4232–4239. https://doi.org/10.1158/1078-0432.CCR-22- 0655/707466/AM/A-RANDOMIZED-OPEN-LABELMULTICENTER- PHASE-3-STUDY
• 55. van Gorkom, G. N. Y., Boerenkamp, L. S., Gijsbers, B. L. M. G., van Ojik, H. H., Wodzig, W. K. W. H., Wieten, L., Van Elssen, C. H. M. J., & Bos, G. M. J. (2022). No Effect of Vitamin C Administration on Neutrophil Recovery in Autologous Stem Cell Transplantation for Myeloma or Lymphoma: A Blinded, Randomized Placebo-Controlled Trial. Nutrients. 2022, Vol. 14, Page 4784, 14(22), 4784. https://doi.org/10.3390/ NU14224784
• 56. Park, J. Y., Baek, J. W., Yu, J., Kim, C. S., Bae, J., & Kim, Y. K. (2023). Vitamin C and catheter-related bladder discomfort after transurethral resection of bladder tumor: A doubleblind, randomized, placebo-controlled study. J Clin Anesth. 89, 111191. https://doi.org/10.1016/J.JCLINANE.2023.111191
• 57. Gillberg, L., Ørskov, A. D., Nasif, A., Ohtani, H., Madaj, Z., Hansen, J. W., Rapin, N., Mogensen, J. B., Liu, M., Dufva, I. H., Lykkesfeldt, J., Hajkova, P., Jones, P. A., & Grønbæk, K. (2019). Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes. Clin Epigenetics. 11(1), 1–11. https://doi.org/10.1186/S13148-019-0739-5/ FIGURES/4