Vitamin C in cancer
Despite the fact that the effectiveness of this supportive therapy has been amply demonstrated in these and subsequent studies, the debate over the use of vitamin C in cancer treatment has made history. The reason for this is because the outcomes of several studies depended on whether the vitamin C was taken orally or intravenously, as well as on how much was administered. Consequently, it was shown that the positive effects of administering vitamin C as supportive therapy in cancer were only apparent when plasma vitamin C levels exceeded a certain limit, which could only be attained by intravenous administration.
Therapeutic effects of vitamin C in cancer
Cancer patients suffer from vitamin C deficiencyFirst, it has been discovered that vitamin C deficiency was common among cancer patients (2), and that those with the lowest vitamin C levels had the shortest survival rates. It's interesting to note that malignant disease symptoms like fatigue, dyspnea, anorexia, and depression are also frequently associated with vitamin C deficiency. It has also been discovered that low plasma vitamin C levels are associated not only with a lower consumption of vitamin C-containing foods, but also with a significant decrease in albumin, an increase in platelet count, and especially in the C-reactive protein, which indicates increased inflammation, i.e. the environment conducive to cancer progression (3).
Studies dating back to the early 1970s(4) and continuing to this day have demonstrated that those who receive regular high doses of vitamin C have an unexpectedly long life span (5). What are the mechanisms by which vitamin C can significantly aid in the treatment of cancer?
Through its oxidative effect, vitamin C contributes to tumor cell deathFirst off, high dosages of vitamin C administered intravenously with plasma values over 20 μmol/L have an oxidative effect that disturbs the metabolism of the tumor cell and may aid in its destruction. This result is brought on by the autooxidation of vitamin C in the presence of Fe3+ ions, which elevates the amounts of free radicals O2- and H2O2 in the tumor cell. As a result, intracellular iron metabolism is disrupted and the tumor cell dies (6).
The phenomena are a little more complicated because once dehydroascorbic acid (DHA), an oxidized form of ascorbate, enters the tumor cell via overexpressed Glut 1 channels (7), it is quickly reduced to ascorbate by intracellular glutathione. This is because cancer cells produce large amounts of intracellular glutathione specifically to protect against the excessive prooxidative metabolism that is characteristic of these cells.
Ascorbate, once inside the cell through autooxidation brought on by the presence of Fe3+, but also through the oxidation of glutathione, raises the degree of oxidative stress and, as a consequence, increases the probability of destruction of the tumor cell.
Because the tumor cell has far more iron than the normal cell and is far more sensitive to oxidative stress, it is vulnerable to vitamin C toxicity. The same cannot be said about normal cells, which typically produce far less free radical species and have significantly lower iron content than tumor cells. Therefore, vitamin C's harmful effects only affect cancerous cells.
Vitamin C in the epigenetic cancer therapyTumor cell epigenetic reprogramming primarily involves DNA hypermethylation, which blocks the expression of tumor suppressor genes, which in turn block the tumor process. This phenomenon is caused by the loss of function of the ten-eleven translocation (TET) proteins that conduct this demethylation process. However, vitamin C is an important cofactor in the optimal activity of TET proteins, precisely because it can donate an electron to the Fe3+ ion, resulting in the active form of iron, Fe2+, which is essential in the demethylation activity of TET proteins.
In fact, experiments have showed that vitamin C supplementation restores the TET2 phenotype and causes DNA demethylation. In this context, vitamin C increases chemosensitivity in vitro by increasing the expression levels of suppressor genes for the tumor process (8). The same has been discovered for blood cancer cells and melanoma cells (9).
Epigenetic therapies are becoming increasingly relevant in cancer treatment, as cancer development and progression are connected to epigenetic changes that block the regulatory mechanisms of the tumor process. In this context, vitamin C supplementation is essential due to its ability to support the activity of TET proteins and JHDM enzymes(10), which are responsible for DNA demethylation activity, i.e. the regulation of pro-cancer epigenetic alterations.
Vitamin C inhibits HIF1 activity, which is essential for cancer invasion, metastasis and progressionSolid tumors typically experience hypoxia because of their rapid growth, which surpasses the capacity of new blood vessels to form, as well as because the existing blood vessels get obstructed. To adapt to this hypoxic environment, tumor cells activate the transcription factor HIF1 (hetero-dimeric transcription factor), which leads to the expression of a very large number of genes supporting both VEGF growth factor stimulation and glycolysis, as well as other cellular mechanisms responsible for cancer invasion, metastasis, and progression (11).
Under normal settings, factor HIF1 activity is regulated by two types of enzymes from the prolyl hydroxylase (PHD1, PHD2, and PHD3) and asparaginyl hydroxylase (factor-inhibiting HIF (FIH)) domains. By hydroxylation of HIF1 prolyl or asparaginyl residues, these enzymes inhibit the transcriptional activity of HIF1 by degrading it (12). However, research has shown that vitamin C is essential for the proper functioning of these enzymes. According to studies, ascorbate levels are thus closely correlated with the suppression of HIF1 transcription factor activity, and consequently, with the suppression of tumor growth (13).
Vitamin C enhances the immune system's response to inflammation and cancerThe increased intracellular concentration of vitamin C has led researchers to validate its beneficial role in the functioning of leukocytes, which are extremely important in the immunological response.
Newer research, as previously indicated, reveals that vitamin C is essential not only in demethylation processes, but also in modulating the transcription factor HIF1, offering new light on the impact of ascorbate in immunological processes.
It has been reported, for example, that vitamin C plays a vital role in many aspects of the immune response, including those mediated by TET 2 mutations with involvement in epigenetic programming, in the differentiation of bone marrow stem cells (14), but also those mediated by conditions of hypoxia and inflammation, in which the translocation factor HIF1 is found to be involved.
Vitamin C will therefore play a significant part in immune regulatory processes as it is a cofactor of both TET2 and hydroxylase activity. Here are a few examples of how ascorbate is involved in these processes:
● By regulating HIF1 expression, vitamin C prevents tumor infiltration by macrophages (15) and tumor cytotoxic T-cell activity suppression (16), and thus slows the progression of tumors (17).
● Vitamin C contributes to the differentiation of lymphocytes and increases the number of circulating lymphocytes (18). Additionally, ascorbate is required for the maturation of T cells (19) and the differentiation of functional T lymphocytes (20) and NK (Natural Killer) cells (21).
● Through the TET2 stimulation mechanism, vitamin C contributes to the repression of the late proinflammatory response based on IL-6, MCP-1, and MCP-3 (22). TET2 is also found to play an important role in TH1 and TH17 cell differentiation, in the formation of memory CD8+ T cells and PD-1 expression in CD4+ effector T cells, as well as in the development, proliferation, and function of NKT cells (23).
Vitamin C has an anti-inflammatory effect● it helps to reduce oxidative stress, TNFa (24) and cytokine levels (25),
● it is a kinase inhibitor (26),
● it inhibits the activation of NFk-b factor (27) and consequently the pro-inflammatory cytokines TNFα, IL-1, IL-8 (28).
● The study by Mikirova and colleagues shows that vitamin C has a significant anti-inflammatory effect in cancer by inhibiting the proinflammatory cytokines IL-1, IL-2, IL-8, as well as the TNF-α, the chemokine eotaxin and the C-reactive protein after treatment with high-dose sodium ascorbate administered intravenously (29).
- Cameron, Ewan, and Allan Campbell. "The orthomolecular treatment of cancer II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer." Chemico-biological interactions 9.4 (1974): 285-315; Cameron, Ewan, and Linus Pauling. "Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer." Proceedings of the National Academy of Sciences 75.9 (1978): 4538-4542.
- Anthony, H. M., and C. J. Schorah. "Severe hypovitaminosis C in lung-cancer patients: the utilization of vitamin C in surgical repair and lymphocyte-related host resistance." British journal of cancer 46.3 (1982): 354-367; Fiaschi, A. I., et al. "Glutathione, ascorbic acid and antioxidant enzymes in the tumor tissue and blood of patients with oral squamous cell carcinoma." European review for medical and pharmacological sciences 9.6 (2005): 361; Choi, Min-Ah, Byung-Sick Kim, and Rina Yu. "Serum antioxidative vitamin levels and lipid peroxidation in gastric carcinoma patients." Cancer letters 136.1 (1999): 89-93.
- Mayland, Catriona R., Michael I. Bennett, and Keith Allan. "Vitamin C deficiency in cancer patients." Palliative medicine 19.1 (2005): 17-20.Cameron, Ewan, and Linus Pauling. "Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer." Proceedings of the National Academy of Sciences 73.10 (1976): 3685-3689.
- Padayatty, Sebastian J., et al. "Intravenously administered vitamin C as cancer therapy: three cases." Cmaj 174.7 (2006): 937-942.
- Schoenfeld, Joshua D., 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 31.4 (2017): 487-500.
- Yun, Jihye, et al. "Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells." Science 325.5947 (2009): 1555-1559.
- Shenoy, Niraj, et al. "Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells." Blood cancer journal 7.7 (2017): e587-e587.
- Gustafson, Christopher B., et al. "Epigenetic reprogramming of melanoma cells by vitamin C treatment." Clinical epigenetics 7.1 (2015): 1-11; Peng, Ding, et al. "Vitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer." Clinical epigenetics 10.1 (2018): 1-13.
- Gillberg, Linn, et al. "Vitamin C–A new player in regulation of the cancer epigenome." Seminars in cancer biology. Vol. 51. Academic Press, 2018.
- Pezzuto, Aldo, and Elisabetta Carico. "Role of HIF-1 in cancer progression: novel insights. A review." Current molecular medicine 18.6 (2018): 343-351; Peng, Kesong, et al. "Histone demethylase JMJD2D activates HIF1 signaling pathway via multiple mechanisms to promote colorectal cancer glycolysis and progression." Oncogene 39.47 (2020): 7076-7091; You, Li, et al. "The role of hypoxia‐inducible factor 1 in tumor immune evasion." Medicinal research reviews 41.3 (2021): 1622-1643.
- Vissers MCM & Das AB Potential mechanisms of action for vitamin C in cancer: reviewing the evidence. Front. Physiol 9, 809 (2018).
- Wilkes, Justin G., et al. "Pharmacologic ascorbate (P-AscH−) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma." Clinical & experimental metastasis 35.1 (2018): 37-51; Jóźwiak, Paweł, et al. "Expression of hypoxia inducible factor 1α and 2α and its association with vitamin C level in thyroid lesions." Journal of Biomedical Science 24.1 (2017): 1-10; Campbell, Elizabeth J., et al. "Restoring physiological levels of ascorbate slows tumor growth and moderates HIF‐1 pathway activity in Gulo−/− mice." Cancer medicine 4.2 (2015): 303-314.
- Mastrangelo, Domenico, et al. "Mechanisms of anti-cancer effects of ascorbate: Cytotoxic activity and epigenetic modulation." Blood Cells, Molecules, and Diseases 69 (2018): 57-64; Mingay, Matthew, et al. "Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia." Leukemia 32.1 (2018): 11-20.
- Imtiyaz, Hongxia Z., et al. "Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation." The Journal of clinical investigation 120.8 (2010).
- Noman, Muhammad Zaeem, et al. "PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation." Journal of Experimental Medicine 211.5 (2014): 781-790; Doedens, Andrew L., et al. "Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression." Cancer research 70.19 (2010): 7465-7475.
- Imtiyaz, Hongxia Z., et al. "Hypoxia-inducible factor 2α regulates macrophage function in mouse models of acute and tumor inflammation." The Journal of clinical investigation 120.8 (2010); Henke, Nina, et al. "Loss of HIF-1β in macrophages attenuates AhR/ARNT-mediated tumorigenesis in a PAH-driven tumor model." Oncotarget 7.18 (2016): 25915.
- Fraser, Robin C., et al. "The effect of variations in vitamin C intake on the cellular immune response of guinea pigs." The American Journal of Clinical Nutrition 33.4 (1980): 839-847; Kennes, Bernard, et al. "Effect of vitamin C supplements on cell-mediated immunity in old people." Gerontology 29.5 (1983): 305-310; Uchio, Ryusei, et al. "High dietary intake of vitamin C suppresses age-related thymic atrophy and contributes to the maintenance of immune cells in vitamin C-deficient senescence marker protein-30 knockout mice." British Journal of Nutrition 113.4 (2015): 603-609.
- Manning, J.; Mitchell, B.; Appadurai, D.A.; Shakya, A.; Pierce, L.J.; Wang, H.; Nganga, V.; Swanson, P.C.; May, J.M.; Tantin, D.; et al. Vitamin C promotes maturation of T-cells. Antioxid. Redox Signal. 2013, 19, 2054–2067.
- Huijskens, Mirelle JAJ, et al. "Technical Advance: Ascorbic acid induces development of double‐positive T cells from human hematopoietic stem cells in the absence of stromal cells." Journal of Leukocyte Biology 96.6 (2014): 1165-1175; Manning, Jared, et al. "Vitamin C promotes maturation of T-cells." Antioxidants & redox signaling 19.17 (2013): 2054-2067.
- Huijskens, Mirelle JAJ, et al. "Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy." Cytotherapy 17.5 (2015): 613-620.
- Zhang, Qian, et al. "Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6." Nature 525.7569 (2015): 389-393.
- Tsagaratou, Ageliki, et al. "TET proteins regulate the lineage specification and TCR-mediated expansion of i NKT cells." Nature immunology 18.1 (2017): 45-53; Beyaz, Semir, et al. "The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells." Nature immunology 18.2 (2017): 184-195.
- Chen, Y.; Luo, G.; Yuan, J.; Wang, Y.; Yang, X.; Wang, X.; Li, G.; Liu, Z.; Zhong, N. Vitamin C mitigates oxidative stress and tumor necrosis factor-alpha in severe community-acquired pneumonia and LPS-induced macrophages. Mediat. Inflamm. 2014.
- Chen, Y.; Luo, G.; Yuan, J.; Wang, Y.; Yang, X.; Wang, X.; Li, G.; Liu, Z.; Zhong, N. Vitamin C mitigates oxidative stress and tumor necrosis factor-alpha in severe community-acquired pneumonia and LPS-induced macrophages. Mediators Inflamm. 2014, 2014, 426740.
- Cárcamo, J.M.; Pedraza, A.; Bórquez-Ojeda, O.; Zhang, B.; Sanchez, R.; Golde, D.W. Vitamin C is a kinase inhibitor: Dehydroascorbic acid inhibits IkappaBalpha kinase beta. Mol. Cell. Biol. 2004, 24, 6645–6652.
- Ferrada, Luciano, et al. "Two distinct faces of vitamin C: AA vs. DHA." Antioxidants 10.2 (2021): 215; Fisher, B.J.; Seropian, I.M.; Kraskauskas, D.; Thakkar, J.N.; Voelkel, N.F.; Fowler, A.A.; Natarajan, R. Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit. Care Med. 2011, 39, 1454–1460; Bowie, A.G.; O’Neill, L.A.J. Vitamin C Inhibits NF-kB Activation by TNF Via the Activation of p38 Mitogen-Activated Protein Kinase. J. Immunol. 2000, 165, 7180–7188.
- Chen, Y.; Luo, G.; Yuan, J.; Wang, Y.; Yang, X.; Wang, X.; Li, G.; Liu, Z.; Zhong, N. Vitamin C mitigates oxidative stress and tumor necrosis factor-alpha in severe community-acquired pneumonia and LPS-induced macrophages. Mediators Inflamm. 2014, 2014, 42674.
- Mikirova, Nina, et al. "Effect of high-dose intravenous vitamin C on inflammation in cancer patients." Journal of translational medicine 10.1 (2012): 1-10.