The anti-tumor mechanism of vitamin C

ZHAO Wen-zhi; SHI Han-ping

doi:10.16689/j.cnki.cn11－9349/r.2019.04.004

PDF(1447 KB)

Electronic Journal of Metabolism and Nutrition of Cancer ›› 2019, Vol. 6 ›› Issue (4) : 409-414. DOI: 10.16689/j.cnki.cn11－9349/r.2019.04.004

The anti-tumor mechanism of vitamin C

ZHAO Wen-zhi, SHI Han-ping

Author information +

History +

Abstract

Vitamin C is an essential nutrient with important physiological function of anti-oxidant activity, anti-aging activity, preventing and treating iron deficiency anemia, being involved in synthesis of collagen, carnitine, catecholamines, and aminopeptide hormones, and biochemical reaction of hydroxylation of transcription factors. It has been nearly half a century since the beginning of researches of anti-tumor effect of vitamin C and the effect was challenged and verified repeatedly. At present, there are three main hypotheses about the anti-tumor mechanism of vitamin C, that is targeting redox imbalance to kill tumor cells, or targeting epigenetic regulators or targeting hypoxia-inducible factor 1（HIF-1） signaling to reduce the malignancy and enhance the sensitivity to treatment of cancer cells. In the mechanism of targeting redox imbalance, intracellular energy is exhausted due to the generation of H2O2 or the oxidation and reduction of the dehydroascorbic acid. In the mechanism of targeting epigenetic regulators, malignancy of the tumor cells is reducing through demethylation of DNA or histone catalyzed by enhancing activity of the related enzyme. In the mechanism of targeting HIF-1, malignancy of the tumor cells is reducing through inhibiting transcription of HIF-1 by enhancing activity of HIF hydroxylase. Its controversial about the efficiency and the prospect of vitamin C in treatment of cancer, which has led to the exploration of the question of drug sensitivity and dosage. Research on the anti-tumor effect of vitamin C is expected to provide a new way for the treatment of cancer.

Key words

Vitamin C / Pro-oxidative stress / Demethylation / Hypoxia-inducible factor

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

ZHAO Wen-zhi, SHI Han-ping. The anti-tumor mechanism of vitamin C[J]. Electronic Journal of Metabolism and Nutrition of Cancer. 2019, 6(4): 409-414 https://doi.org/10.16689/j.cnki.cn11－9349/r.2019.04.004

References

1.孙长颢. 营养与食品卫生学.第8版. 北京: 人民卫生出版社,2018.
2.Corti A, Casini AF, Pompella A. Cellular pathways for transport and efflux of ascorbate and dehydroascorbate. Arch Biochem Biophys. 2010；500（2）:107-115.
3.Wilson JX. The physiological role of dehydroascorbic acid. FEBS Lett. 2002；527（1-3）:5-9.
4.Mandl J, Szarka A, Banhegyi G. Vitamin C: update on physiology and pharmacology. Br J Pharmacol. 2009；157（7）:1097-1110.
5.Englard S, Seifter S. The biochemical functions of ascorbic acid. Annu Rev Nutr.1986；6:365-406.
6.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（4）:285-315.
7.Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A.1976；73（10）:3685-3689.
8.Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A. 1978；75（9）:4538-4542.
9.Creagan ET, Moertel CG, OFallon JR, et al. Failure of high-dose vitamin C （ascorbic acid） therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med.1979；301（13）:687-690.
10.Moertel CG, Fleming TR, Creagan ET, et al. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med.1985；312（3）:137-141.
11.Chen Q, Espey MG, Sun AY, et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci U S A. 2007；104（21）:8749-8754.
12.Carr AC, Cook J. Intravenous vitamin C for cancer therapy - identifying the current gaps in our knowledge. Front Physiol. 2018；9:1182.
13.Nielsen TK, Hojgaard M, Andersen JT, et al. Elimination of ascorbic acid after high-dose infusion in prostate cancer patients: a pharmacokinetic evaluation. Basic Clin Pharmacol Toxicol. 2015；116（4）:343-348.
14.张婷,饶本强,江波.维生素C在肿瘤治疗中的作用. 肿瘤代谢与营养电子杂志. 2016；3（3）:135-138.
15.Duarte TL, Almeida GM, Jones GD. Investigation of the role of extracellular H2O2 and transition metal ions in the genotoxic action of ascorbic acid in cell culture models. Toxicol Lett. 2007；170（1）:57-65.
16.Lee YJ, Shacter E. Oxidative stress inhibits apoptosis in human lymphoma cells. J Biol Chem.1999；274（28）:19792-19798.
17.Schraufstatter IU, Hinshaw DB, Hyslop PA, et al. Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide. J Clin Invest.1986；77（4）:1312-1320.
18.Kroemer G. Mitochondria in cancer. Oncogene. 2006；25（34）:4630-4632.
19.Ahmad IM, Aykin-Burns N, Sim JE, et al. Mitochondrial O2*-and H2O2 mediate glucose deprivation-induced stress in human cancer cells. J Biol Chem. 2005；280（6）:4254-4263.
20.Comelli M, Di Pancrazio F, Mavelli I. Apoptosis is induced by decline of mitochondrial ATP synthesis in erythroleukemia cells. Free Radic Biol Med. 2003；34（9）:1190-1199.
21.DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv. 2016；2（5）:e1600200.
22.Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016；41（3）:211-218.
23.Parker WH, Qu ZC, May JM. Ascorbic acid transport in brain microvascular pericytes. Biochem Biophys Res Commun. 2015；458（2）:262-267.
24.Corpe CP, Eck P, Wang J, et al. Intestinal dehydroascorbic acid （DHA） transport mediated by the facilitative sugar transporters, GLUT2 and GLUT8. J Biol Chem. 2013；288（13）:9092-9101.
25.Lu YX, Wu QN, Chen DL, et al. Pharmacological ascorbate suppresses growth of gastric cancer cells with glut1 overexpression and enhances the efficacy of oxaliplatin through redox modulation. Theranostics. 2018；8（5）:1312-1326.
26.Yun J, Mullarky E, Lu C, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015；350（6266）:1391-1396.
27.Linster CL, Van Schaftingen E. Vitamin C. Biosynthesis, recycling and degradation in mammals. FEBS J. 2007；274（1）:1-22.
28.杨柳青, 石汉平. 维生素C对KRAS突变型结直肠癌的治疗作用. 肿瘤代谢与营养电子杂志. 2015；2（4）:76-79.
29.Cimmino L, Neel BG, Aifantis I. Vitamin C in stem cell reprogramming and cancer. Trends Cell Biol. 2018；28（9）:698-708.
30.Gillberg L, Orskov AD, Liu M, et al. Vitamin C - A new player in regulation of the cancer epigenome. Semin Cancer Biol. 2018；51:59-67.
31.Agathocleous M, Meacham CE, Burgess RJ, et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. 2017；549（7673）:476-481.
32.Cimmino L, Dolgalev I, Wang Y, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. 2017；170（6）:1079-1095.
33.Shenoy N, Bhagat T, Nieves E, et al. Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. Blood Cancer J. 2017；7（7）:e587.
34.Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011；11（10）:726-734.
35.Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014；124（17）:2705-2712.
36.Hu CY, Mohtat D, Yu Y, et al. Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival. Clin Cancer Res. 2014；20（16）:4349-4360.
37.Jiang Y, Dunbar A, Gondek LP, et al. Aberrant DNA methylation is a dominant mechanism in MDS progression to AML. Blood. 2009；113（6）:1315-1325.
38.Letouze E, Martinelli C, Loriot C, et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell. 2013；23（6）:739-752.
39.Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2016 update on diagnosis, risk stratification, and management. Am J Hematol. 2016；91（6）:631-642.
40.Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 2016；30（7）:733-750.
41.Wu SC, Zhang Y. Active DNA demethylation: many roads lead to Rome. Nat Rev Mol Cell Biol. 2010；11（9）:607-620.
42.He YF, Li BZ, Li Z, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011；333（6047）:1303-1307.
43.Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature. 2013；502（7472）:472-479.
44.Lian CG, Xu Y, Ceol C, et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell. 2012；150（6）:1135-1146.
45.Tsukada Y, Fang J, Erdjument-Bromage H, et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature. 2006；439（7078）:811-816.
46.Suzuki T, Minehata K, Akagi K, et al. Tumor suppressor gene identification using retroviral insertional mutagenesis in Blm-deficient mice. EMBO J. 2006；25（14）:3422-3431.
47.Mustafi S, Camarena V, Volmar CH, et al. Vitamin C sensitizes melanoma to BET inhibitors. Cancer Res. 2018；78（2）:572-583.
48.Peng D, Ge G, Gong Y, et al. Vitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer. Clin Epigenetics. 2018；10（1）:94.
49.Masoud GN, Li W. HIF-1alpha pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B. 2015；5（5）:378-389.
50.Kuiper C, Dachs GU, Currie MJ, et al. Intracellular ascorbate enhances hypoxia-inducible factor （HIF）-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. Free Radic Biol Med. 2014；69:308-317.
51.Vadde R, Vemula S, Jinka R, et al. Role of hypoxia-inducible factors （HIF） in the maintenance of stemness and malignancy of colorectal cancer. Crit Rev Oncol Hematol. 2017；113:22-27.
52.Koivunen P, Hirsila M, Gunzler V, et al. Catalytic properties of the asparaginyl hydroxylase （FIH） in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J Biol Chem. 2004；279（11）:9899-9904.
53.Lando D, Peet DJ, Gorman JJ, et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 2002；16（12）:1466-1471.
54.Ngo B, Van Riper JM, Cantley LC, et al. Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer. 2019；19（5）:271-282.
55.Kuiper C, Dachs GU, Currie MJ, et al. Intracellular ascorbate enhances hypoxia-inducible factor （HIF）-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. Free Radic Biol Med. 2014；69:308-317.
56.Jozwiak P, Ciesielski P, Zaczek A, et al. Expression of hypoxia inducible factor 1alpha and 2alpha and its association with vitamin C level in thyroid lesions. J Biomed Sci. 2017；24（1）:83.
57.Wohlrab C, Vissers M, Phillips E, et al. The association between ascorbate and the hypoxia-inducible factors in human renal cell carcinoma requires a functional von hippel-lindau protein. Front Oncol. 2018；8:574.
58.Kuiper C, Molenaar IG, Dachs GU, et al. Low ascorbate levels are associated with increased hypoxia-inducible factor-1 activity and an aggressive tumor phenotype in endometrial cancer. Cancer Res. 2010；70（14）:5749-5758.
59.Campbell EJ, Vissers MC, Dachs GU. Ascorbate availability affects tumor implantation-take rate and increases tumor rejection in Gulo（-/-） mice. Hypoxia （Auckl）. 2016；4:41-52.
60.徐一杰, 王志超, 侯高峰, 等. 大剂量维生素C在肿瘤患者应用的安全性观察. 肿瘤代谢与营养电子杂志. 2018；5（4）:399-402.