Vitamin C in cancer

Discovered almost 80 years ago, vitamin C has been clinically tested in the treatment of cancer since the 1970s. Clinical investigations on the effects of vitamin C on cancer began around the same period, with early studies mostly conducted by Cameron and Pauling (1).

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 deficiency

First, 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 death

First 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 therapy

Tumor 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 progression

Solid 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 cancer

The 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).

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