Vitamin C (VitC), also known as L-ascorbic acid, is a water-soluble vitamin commonly found in most vegetables and fruits. Based on its physiochemical characteristics, the known effects can be divided into two categories. First, it directly involves in human immune regulation as an antioxidant (i.e. reducing agent) to provide anti-cancer, anti-aging, enhancing immunity effects and reduce the incidence of cardiovascular diseases. The second is to act as a cofactor or enzyme to catalyze the synthesis of collagen, neurotransmitters and modulate DNA expression [1]. Human body cannot synthesize vitamin C so it has to be supplemented from food.
Its anti-tumoral effects have been controversial. As early as 1976, E. Cameron and L. Pauling found that oral and intravenous administration of VitC prolonged the survival of cancer patients in the late stages [2]. However, the subsequent double-blind clinical trial failed to draw the same conclusion because oral supplementation did not show significant clinical effects. Studies found that administration modes would significantly influence the pharmacokinetics of VitC, and the maximum dose achieved by oral supplementation was far less than that by intravenous administration [3].
On February 26, 2020, the research team from Turin University published a paper at Science Translational Medicine, claiming the efficacy of high-dose VitC (1.5 g/kg for mice) in participating in immune regulation and inhibiting tumor growth. The team selected four cancer models of mouse: rectal, breast, pancreatic cancer and melanoma. One hour after the intravenous administration, the subject mice exhibited slower tumor growth and DNA damage within the tumor tissue, induced by oxidative stress [4]. Notably, a fully functional immune system was required for VitC to show its effectiveness because mice of compromised immune system showed no significant difference before and after VitC supplementation. These results further confirmed that VitC introduces anticancer effects by enhancing immunity. In addition, Yun et al. from Weill Cornell Medical College found that high-dose VitC induced energy crisis of cancer cells by blocking glycolysis, thus selectively starving the cancer cells [5].
Glycolysis refers to the process in which glucose is catabolized into pyruvate. Glycolysis yields a small amount of energy, because its main purpose is to provide raw materials for other biosynthesis. The tricarboxylic acid cycle into which pyruvate enters is the main energy source for somatic cells, and this cycle requires participation of oxygen. According to the Warburg hypothesis, cells that grow too fast often suffer from oxygen shortage and cannot effectively circulate tricarboxylic acid, so their energy mainly comes from glycolysis. This is the scenario of cancer cells. Since glycolysis releases very limited energy, a large amount of glucose is needed to maintain the vast energy consumption [6]. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an indispensable enzyme in glycolysis. KARS and BRAF are the driver genes of colon cancer. More than half of rectal cancer patients have at least one of these mutations, which up-regulate the expression of GLUT1 (glucose transporter) to enhance the uptake of glucose to meet the vigorous demand of cancer cells for energy.
There are two ways for VitC to cross the cell membrane, by the sodium-VitC cotransporter and GLUT. The former transport reduced VitC thus would not cause intracellular oxidative stress, but the latter only transport oxidized VitC, that is, dehydroascorbic acid (DHA). DHA is then reduced back to VitC inside the cells, at the cost of consuming intracellular reductive substances such as glutathione (GSH), thioredox protein and NADPH. After reductive substances are depleted, oxidative stress develops and reactive oxygen species (ROS) accumulate. ROS blocks glycolysis by inactivating GAPDH. This renders cancer cells to be "starved to death". In addition, ROS also cause irreversible oxidative damage to DNA, as described above. Overexpressed GLUT1 imports more DHA into cancer cells, and then the reduction of DHA depletes intracellular reductive substances excessively and causes oxidative stress. ROS not only blocks glycolysis, but also attacks DNA. This is how high-dose VitC selectively kills cancer cells. Although high-dose VitC can also affect somatic cells, the effect is very limited, far from detrimental.
The daily requirement of VitC for adults is ~50 mg, while the dose required to exhibit anti-tumoral effects is ~2000 mg. Oral supplementation will never reach this threshold so clinically intravenous administration is preferred [7]. A clinical trial was conducted by researchers at the University of Iowa, in which high-dose VitC (800-1000 times of the recommended daily dose) was injected to patients diagnosed of brain and lung cancer on a regular basis. This high-dose VitC was proved not only safe, but also slowed down the tumor development [8]. However, there are other studies pointing out that VitC interfered with some anticancer drugs e.g. tamoxifen [9]. It is worth noticing that VitC has not been officially listed as an anti-cancer drug, and whether there are antagonistic or synergic effects with other anti-cancer drugs remains unclear.
References
[1] https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/#h7
[2] E. Cameron, L. Pauling, Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. U.S.A. 73, 3685–3689 (1976).
[3] S. J. Padayatty, H. Sun, Y. Wang, H. D. Riordan, S. M. Hewitt, A. Katz, R. A. Wesley, M. Levine, Vitamin C pharmacokinetics: Implications for oral and intravenous use. Ann. Intern. Med. 140, 533–537 (2004).
[4] A. Magrì, G. Germano, A. Lorenzato, S. Lamba, R. Chilà, M. Montone, V. Amodio, T. Ceruti, F. Sassi, S. Arena, S. Abrignani, M. D’Incalci, M. Zucchetti, F. D. Nicolantonio, A. Bardelli, High-dose vitamin C enhances cancer immunotherapy, Science Translational Medicine 12 (2020), doi:10.1126/scitranslmed.aay8707.
[5] J. Yun, E. Mullarky, C. Lu, K. N. Bosch, A. Kavalier, K. Rivera, J. Roper, I. I. C. Chio, E. G. Giannopoulou, C. Rago, A. Muley, J. M. Asara, J. Paik, O. Elemento, Z. Chen, D. J. Pappin, L. E. Dow, N. Papadopoulos, S. S. Gross, L. C. Cantley, Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH, Science 350, 1391–1396 (2015).
[6] D. Deng, C. Xu, P. Sun, J. Wu, C. Yan, M. Hu, N. Yan, Crystal structure of the human glucose transporter GLUT1, Nature 510, 121–125 (2014).
[7] https://www.cancer.gov/about-cancer/treatment/cam/patient/vitamin-c-pdq#link/_19
[8] https://www.radioiowa.com/2018/11/19/u-i-starting-new-trials-of-vitamin-c-treatment-against-cancer/
[9] T. Subramani, S. K. Yeap, W. Y. Ho, C. L. Ho, A. R. Omar, S. A. Aziz, Nik Mohd. Afizan Nik Abd. Rahman, N. B. Alitheen, Vitamin C suppresses cell death in MCF-7 human breast cancer cells induced by tamoxifen, Journal of Cellular and Molecular Medicine 18, 305–313 (2013).