Vitamin C in Treatment of Patients with Cancer

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1		Gwendolyn N.Y. Van Gorkom	--	1248	2022-08-03 13:38:23	\|
2	format change	Peter Tang	-40 word(s)	1208	2022-08-04 03:47:23	\|

This entry is adapted from the peer-reviewed paper 10.3390/nu11050977

Vitamin C is an essential micronutrient, that plays an important role in numerous physiological processes in the human body. Vitamin C stimulates the production and activation of immune cells, so perhaps supplementation could be used to improve the immunity in cancer patients .

vitamin C ascorbic acid cancer supplementation overall survival adverse events

1. Introduction

Vitamin C is an essential micronutrient, that plays an important role in numerous physiological processes in the human body. Unlike most mammals, humans lack the ability to generate endogenous vitamin C due to a mutation in the GULO gene and are thereby completely dependent on dietary intake. The biological efficacy of vitamin C depends on its redox abilities and it functions as a cofactor in many enzymatic reactions. In physiological concentrations, it also functions as an antioxidant.

By the 1970s, Nobel Price winner Linus Pauling had already developed a strategy to use intravenous (IV) vitamin C in cancer patients ^[1]^[2]. He treated patients with advanced cancer with high doses of vitamin C and reported a positive effect on survival. However, these studies have been methodologically criticized on several aspects such as data collection and data analysis. This resulted in a limited use of vitamin C in cancer patients. Other studies performed afterwards could also not reproduce these results; however, opposed to the intravenous use of vitamin C by Pauling et al, in most of these studies, oral vitamin C supplementation was used ^[3]. Pharmacokinetic studies show that the way of administration makes a big difference as peak plasma vitamin C concentrations after intravenous administration are much higher (up to 70-fold) than after oral intake ^[4]. Peak plasma concentrations also continue to increase when the intravenous dose of vitamin C is increased, while peak plasma concentrations plateau around 220 µM even though oral doses are increased.

There are multiple hypotheses about the way vitamin C has anti-tumor effects. An important possible mechanism of action is that in pharmacological concentrations (especially after intravenous use) vitamin C functions as a pro-oxidant and stimulates the formation of hydrogen peroxide. This hydrogen peroxide can create reactive oxygen species (ROS), that directly have cytotoxic activity on cancer cells ^[5]. Another important hypothesis is that vitamin C can create important epigenetic changes due to its effect on 2-oxoglutarate-dependent dioxygenases, like histone and DNA demethylases ^[6]. In preclinical studies investigators also show that vitamin C can have a synergetic effect with some types of chemo- and immunotherapy ^[7]^[8]^[9]^[10]^[11].

Additionally it was shown in pre-clinical studies that vitamin C has an important role in the immune system, as it stimulates the production and/or activation of immune cells, like T-lymphocytes and natural killer cells, that have a function in fighting against pathogens and cancer cells ^[12]^[13]^[14].

In the previous research on vitamin C the researchers noticed that many of the patients receiving intensive chemotherapy and/or stem cell transplantations for hematological malignancies have low vitamin C plasma concentrations ^[15]. This could be the result of low dietary intake of these patients or of an increased need for vitamin C in tumor cells or in immune cells. In extension of the results, other researchers observed that low vitamin C plasma levels in patients with various types of advanced cancer were associated with worse survival ^[16].

2. The Effect of Vitamin C (Ascorbic Acid) in the Treatment of Patients with Cancer

This research presents the results and quality assessment of 19 studies to evaluate the effect of vitamin C treatment in cancer patients. It is difficult to draw any conclusions, since these studies have a large variety of outcome measures and the included studies also differ in study population (from newly diagnosed to advanced cancer), co-interventions (none or various adjuvant anti-cancer treatments), and vitamin C treatment (different doses, schedules and modes of delivery). The results of some studies do suggest that vitamin C might have a positive effect on overall survival, clinical response, QOL and PS. However, this effect cannot be generalized to all patient groups with cancer. The best indication of a positive effect of vitamin C is seen in the RCT where it was used intravenously in elderly acute myeloid leukemia patients who were also treated with decitabine. This effect is most likely due to direct regulation of ten-eleven-translocation (TET) activity by vitamin C in synergy with decitabine. TET enzymes are dioxygenases that are important for DNA methylation and are often less functional in patients with AML. One of the potential working mechanisms of decitabine already is the upregulation of the TET proteins; it is thought that vitamin C enhances this effect ^[17]. In all other studies, especially those that included patients with various types of cancer, the results were less clear. Therefore, it is not proven and seems quite unlikely that the pro-oxidant capacity of vitamin C in high dosage creates a positive effect on overall survival, clinical response, QOL or PS in cancer patients in general.

More than half of the studies that researched QOL or PS saw a beneficial effect. However, since these studies were not blinded, patients may have experienced the well-known ‘placebo effect’. In this respect, the observation of Creagan et al. is important, since he demonstrates a positive effect in nearly 60% of the patients on placebo. These factors might have favored a positive outcome of vitamin C treatment in all studies, especially those in which outcome was assessed through self-administered questionnaires that are highly subjective.

The mode of delivery seems to be an important factor in the effectiveness of the vitamin C treatment. In the studies with positive effects intravenous delivery was used, while the absence of effect was mostly after oral administration. This suggests that the vitamin C levels that can be reached by oral supplementation might not be high enough for a possible effect, or that vitamin C is not absorbed from the gastrointestinal tract.

In the 14 studies in which investigators reported on side effects of vitamin C, these side effects were mostly mild or none at all and could have been related to the cancer itself or to the concomitant therapy patients received. There was no obvious difference in side effects of oral vitamin C compared to intravenous supplementation.

If measured at baseline, only 1 of the studied patient groups was vitamin C deficient. Perhaps supplementation would be more efficient and useful in patient groups that indeed are deficient. Unfortunately, also not many vitamin C plasma concentrations after supplementation were documented, but with oral supplementation plasma concentrations were much lower than with IVC.

3. Conclusions

The results do not prove that there is a clinically relevant positive effect of vitamin C supplementation in most cancer patients on the overall survival, clinical status, QOL and PS. The quality of the studies published is low and the interventions and patient groups are very diverse. The best indication of a positive effect is seen in acute myeloid leukemia patients in combination with decitabine, and in vitro data also show a synergistic efficacy of both treatments. An effect in some other patient groups might still be possible and might have been overlooked. In addition, clear pharmacological data might be needed to optimize treatment plans.

Treatment with vitamin C is likely to be safe, with almost no serious adverse events and minimal mild side effects, even with high doses of intravenous supplementation. There are also no indications that cancer progresses faster under vitamin C supplementation.

References

Cameron, E.; Pauling, L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. USA 1976, 73, 3685–3689.
Cameron, E.; Campbell, A. The orthomolecular treatment of cancer. Ii. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem. Biol. Interact. 1974, 9, 285–315.
Creagan, E.T.; Moertel, C.G.; O’Fallon, J.R.; Schutt, A.J.; O’Connell, M.J.; Rubin, J.; Frytak, S. Failure of high-dose vitamin c (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N. Engl. J. Med. 1979, 301, 687–690.
Padayatty, S.J.; Sun, H.; Wang, Y.; Riordan, H.D.; Hewitt, S.M.; Katz, A.; Wesley, R.A.; Levine, M. Vitamin c pharmacokinetics: Implications for oral and intravenous use. Ann. Intern. Med. 2004, 140, 533–537.
Chen, Q.; Espey, M.G.; Sun, A.Y.; Pooput, C.; Kirk, K.L.; Krishna, M.C.; Khosh, D.B.; Drisko, J.; Levine, M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. USA 2008, 105, 11105–11109.
Young, J.I.; Zuchner, S.; Wang, G. Regulation of the epigenome by vitamin c. Annu. Rev. Nutr. 2015, 35, 545–564.
Kassouf, W.; Highshaw, R.; Nelkin, G.M.; Dinney, C.P.; Kamat, A.M. Vitamins C and K3 sensitize human urothelial tumors to gemcitabine. J. Urol. 2006, 176, 1642–1647.
Bober, P.; Alexovic, M.; Talian, I.; Tomkova, Z.; Viscorova, Z.; Benckova, M.; Andrasina, I.; Ciccocioppo, R.; Petrovic, D.; Adamek, M.; et al. Proteomic analysis of the vitamin C effect on the doxorubicin cytotoxicity in the MCF-7 breast cancer cell line. J. Cancer Res. Clin. Oncol. 2017, 143, 35–42.
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.
Kalita, S.; Verma, A.K.; Prasad, S.B. Chlorambucil and ascorbic acid-mediated anticancer activity and hematological toxicity in Dalton’s ascites lymphoma-bearing mice. Indian J. Exp. Biol. 2014, 52, 112–124.
Kurbacher, C.M.; Wagner, U.; Kolster, B.; Andreotti, P.E.; Krebs, D.; Bruckner, H.W. Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro. Cancer Lett. 1996, 103, 183–189.
Huijskens, M.J.; Walczak, M.; Koller, N.; Briede, J.J.; Senden-Gijsbers, B.L.; Schnijderberg, M.C.; Bos, G.M.; Germeraad, W.T. Technical advance: ascorbic acid induces development of double-positive T cells from human hematopoietic stem cells in the absence of stromal cells. J. leukoc. biol. 2014, 96, 1165–1175.
Huijskens, M.J.; Walczak, M.; Sarkar, S.; Atrafi, F.; Senden-Gijsbers, B.L.; Tilanus, M.G.; Bos, G.M.; Wieten, L.; Germeraad, W.T. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Cytotherapy 2015, 17, 613–620.
Van Gorkom, G.N.Y.; Klein Wolterink, R.G.J.; Van Elssen, C.; Wieten, L.; Germeraad, W.T.V.; Bos, G.M.J. Influence of Vitamin C on Lymphocytes: An Overview. Antioxidants 2018, 7, 41.
Huijskens, M.J.; Wodzig, W.K.; Walczak, M.; Germeraad, W.T.; Bos, G.M. Ascorbic acid serum levels are reduced in patients with hematological malignancies. Result. Immun. 2016, 6, 8–10.
Mayland, C.R.; Bennett, M.I.; Allan, K. Vitamin C deficiency in cancer patients. Palliat. Med. 2005, 19, 17–20.
Zhao, H.; Zhu, H.; Huang, J.; Zhu, Y.; Hong, M.; Zhu, H.; Zhang, J.; Li, S.; Yang, L.; Lian, Y.; et al. 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. 2018, 66, 1–7.

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Subjects: Oncology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Gwendolyn N.Y. van Gorkom

Eline L. Lookermans

Catharina H.M.J. Van Elssen

Gerard M.J. Bos

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Update Date: 04 Aug 2022

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1. Introduction

2. The Effect of Vitamin C (Ascorbic Acid) in the Treatment of Patients with Cancer

3. Conclusions

References