Regulatory role and anticarcinogenic properties of certain vitamins’ active derivatives and vitamin-like substances

• Anastasia A. Zabolotneva
• Olga P. Shatova
• Ilia E. Mikin
• Denis V. Brill
• Sergey A. Roumiantsev

Abstract

Vitamins are low-molecular compounds consisting of an essential part of the human diet. After entering the human organism vitamins or their precursors can undergo chemical modification, changing their biological properties and regulatory activity. For many decades, vitamins were considered mainly as precursors of enzyme cofactors, and hypovitaminosis was interpreted as a deficiency of a particular metabolite resulting from enzyme’s insufficient activity. However, with the development of molecular biology techniques and breakthrough in understanding of gene expression regulation and cell signaling mechanisms, as well as in molecular mechanisms of diseases associated with impaired functions, it became clear that there are significantly more active forms of vitamins, and their functions in the human body are more diverse than it had been suggested previously.

The purpose of this review was to consider vitamins’ and vitamins’ derivatives regulatory and anti-tumor role and their potential for clinical application as main or adjuvant drugs for malignant neoplasms treatment.

Material and methods. The present review is based on the results of literature analysis conducted in the Scopus, PubMed, Science Direct databases for the keywords «vitamin A AND cancer», «retinoids AND cancer», «vitamin D AND cancer», «vitamins AND cancer», «vitamins AND cancer». The search depth was 6 years (2016-2021).

Results. Active forms of hydrophilic and lipophilic vitamins are key participants in the processes of chromatin remodeling, genome stability maintaining, covalent modification of proteins, including signaling and regulatory ones, and also act as chemical messengers themselves. Therefore, vitamin deficiency is associated with autoimmune and chronic diseases such as cancer, atherosclerosis, diabetes mellitus, etc. This review considers the regulatory role of active forms of vitamins, their derivatives and vitamin-like substances as well as their involvement in the process of carcinogenesis.

Conclusions. Modern studies confirm the high therapeutic potential of vitamins: the use of pharmacological doses of vitamins or their derivatives may help to prevent or fight non-communicable diseases, including cancer.

Keywords:vitamins; vitamin-like substances; retinoids; calcitriol; tocopherols; choline; biotin; cancer

Литература/References

1. Chawla J., Kvarnberg D. Hydrosoluble vitamins. Handb Clin Neurol. 2014; 120: 891–914. DOI: https://doi.org/10.1016/B978-0-7020-4087-0.00059-0

2. Zingg J.M. Vitamin E: regulatory role on signal transduction. IUBMB Life. 2019; 71 (4): 456–78. DOI: https://doi.org/10.1002/iub.1986

3. Christakos S., Dhawan P., Verstuyf A., Verlinden L., Carmeliet G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016; 96 (1): 365–408. DOI: https://doi.org/10.1152/physrev.00014.2015

4. Nasir A., Bullo M.M.H., Ahmed Z., Imtiaz A., Yaqoob E., Jadoon M., et al. Nutrigenomics: epigenetics and cancer prevention: a comprehensive review. Crit Rev Food Sci Nutr. 2020; 60 (8): 1375–87. DOI: https://doi.org/10.1080/10408398.2019.1571480

5. El-Sharkawy A., Malki A. Vitamin D signaling in inflammation and cancer: molecular mechanisms and therapeutic implications. Molecules. 2020; 25 (14): 3219. DOI: https://doi.org/10.3390/molecules25143219

6. Peterson C.T., Rodionov D.A., Osterman A.L., Peterson Scott N.B. Vitamins and their role in immune regulation and cancer. Nutrients. 2020; 12 (11): 3380. DOI: https://doi.org/10.3390/nu12113380

7. Jain A., Tiwari A., Verma A., Jain S.K. Vitamins for cancer prevention and treatment: an insight. Curr Mol Med. 2018; 17 (5): 321–40. DOI: https://doi.org/10.2174/1566524018666171205113329

8. Tang X.H., Gudas L.J. Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol. 2011; 6: 345–64. DOI: https://doi.org/10.1146/annurev-pathol-011110-130303

9. Milani A., Basirnejad M., Shahbazi S., Bolhassani A. Carotenoids: biochemistry, pharmacology and treatment. Br J Pharmacol. 2017; 174 11): 1290–324. DOI: https://doi.org/10.1111/bph.13625

10. Alizadeh F., Bolhassani A., Khavari A., Bathaie S. Z., Naji T., Bidgoli S.A. Retinoids and their biological effects against cancer. Int Immunopharmacol. 2014; 18 (1): 43–9. DOI: https://doi.org/10.1016/j.intimp.2013.10.027

11. Szymański Ł., Skopek R., Palusińska M., Schenk T., Stengel S., Lewicki S., et al. Retinoic acid and its derivatives in skin. Cells. 2020; 9 (12): 2660. DOI: https://doi.org/10.3390/cells9122660

12. Garattini E., Bolis M., Garattini S.K., Fratelli M., Centritto F., Paroni G., et al. Retinoids and breast cancer: From basic studies to the clinic and back again. Cancer Treat Rev. 2014; 40 (6): 739–49. DOI: https://doi.org/10.1016/j.ctrv.2014.01.001

13. Ghyselinck N.B., Duester G. Retinoic acid signaling pathways. Development. 2019; 146 (13): dev167502. DOI: https://doi.org/10.1242/dev.167502

14. Uray I.P., Dmitrovsky E., Brown P.H. Retinoids and rexinoids in cancer prevention: from laboratory to clinic. Semin Oncol. 2016; 43 (1): 49–64. DOI: https://doi.org/10.1053/j.seminoncol.2015.09.002

15. Ni X., Hu G., Cai X. The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit Rev Food Sci Nutr. 2019; 59 (sup1): S71–80. DOI: https://doi.org/10.1080/10408398.2018.1509201

16. Haque A., Banik N.L., Ray S.K. Emerging role of combination of all-trans retinoic acid and interferon-gamma as chemoimmunotherapy in the management of human glioblastoma. Neurochem Res. 2007; 32 (12): 2203–9. DOI: https://doi.org/10.1007/s11064-007-9420-z

17. Stahl M., Tallman M.S. Differentiation syndrome in acute promyelocytic leukaemia. Br J Haematol. 2019; 187 (2): 157–62. DOI: https://doi.org/10.1111/bjh.16151

18. Shilkaitis A., Green A., Christov K. Retinoids induce cellular senescence in breast cancer cells by RAR-β dependent and independent pathways: potential clinical implications (Review). Int J Oncol. 2015; 47 (1): 35–42. DOI: https://doi.org/10.3892/ijo.2015.3013

19. He J., Gu Y., Zhang S. Vitamin A and breast cancer survival: a systematic review and meta-analysis. Clin Breast Cancer. 2018; 18 (6): e1389–400. DOI: https://doi.org/10.1016/j.clbc.2018.07.025

20. Doldo E., Costanza G., Agostinelli S., Tarquini C., Ferlosio A., Arcuri G., et al. Vitamin A, cancer treatment and prevention: the new role of cellular retinol binding proteins. Biomed Res Int. 2015; 2015: 1–14. DOI: https://doi.org/10.1155/2015/624627

21. Hara A., Koyama-Nasu R., Takami M., Toyoda T., Aoki T., Ihara F., et al. CD1d expression in glioblastoma is a promising target for NKT cell-based cancer immunotherapy. Cancer Immunol Immunother. 2021; 70 (5): 1239–54. DOI: https://doi.org/10.1007/s00262-020-02742-1

22. Chang S.W., Lee H.C. Vitamin D and health – the missing vitamin in humans. Pediatr Neonatol. 2019; 60 (3): 237–44. DOI: https://doi.org/10.1016/j.pedneo.2019.04.007

23. Saponaro F., Saba A., Zucchi R. An update on vitamin D metabolism. Int J Mol Sci. 2020; 21 (18): 6573. DOI: https://doi.org/10.3390/ijms21186573

24. Jeon S.M., Shin E.A. Exploring vitamin D metabolism and function in cancer. Exp Mol Med. 2018; 50 (4): 1–14. DOI: https://doi.org/10.1038/s12276-018-0038-9

25. Wimalawansa S.J. Vitamin D deficiency: effects on oxidative stress, epigenetics, gene regulation, and aging. Biology. 2019; 8 (2): 30. DOI: https://doi.org/10.3390/biology8020030

26. Nair-Shalliker V., Armstrong B.K., Fenech M. Does vitamin D protect against DNA damage? Mutat Res. 2012; 733 (1–2): 50–7. DOI: https://doi.org/10.1016/j.mrfmmm.2012.02.005

27. Gil Á., Plaza-Diaz J., Mesa M.D. Vitamin D: classic and novel actions. Ann Nutr Metab. 2018; 72 (2): 87–95. DOI: https://doi.org/10.1159/000486536

28. González-Sancho J.M., Larriba M.J., Muñoz A. Wnt and vitamin D at the crossroads in solid cancer. Cancers. 2020; 12 (11): 3434. DOI: https://doi.org/10.3390/cancers12113434

29. Gnagnarella P., Raimondi S., Aristarco V., Johansson H.A., Bellerba F., Corso F., Gandini S. Vitamin D receptor polymorphisms and cancer. Adv Exp Med Biol. 2020; 1268: 53–114. DOI: https://doi.org/10.1007/978-3-030-46227-7_4

30. Ahn J., Park S., Zuniga B., Bera A., Song C.S., Chatterjee B. Vitamin D in prostate cancer. Vitam Horm. 2016; 100: 321–55. DOI: https://doi.org/10.1016/bs.vh.2015.10.012

31. Srinivasan M., Parwani A.V., Hershberger P.A., Lenzner D.E., Weissfeld J.L. Nuclear vitamin D receptor expression is associated with improved survival in non-small cell lung cancer. J Steroid Biochem Mol Biol. 2011; 123 (1–2): 30–6. DOI: https://doi.org/10.1016/j.jsbmb.2010.10.002

32. Jóźwicki W., Brożyna A., Siekiera J., Slominski A. Expression of vitamin D receptor (VDR) positively correlates with survival of urothelial bladder cancer patients. Int J Mol Sci. 2015; 16 (10): 24369–86. DOI: https://doi.org/10.3390/ijms161024369

33. Abraham A., Kattoor A.J., Saldeen T., Mehta J.L. Vitamin E and its anticancer effects. Crit Rev Food Sci Nutr. 2019; 59 (17): 2831–8. DOI: https://doi.org/10.1080/10408398.2018.1474169

34. Jiang Q. Natural forms of vitamin E as effective agents for cancer prevention and therapy. Adv Nutr. 2017; 8 (6): 850–67. DOI: https://doi.org/10.3945/an.117.016329

35. Yang C.S., Luo P., Zeng Z., Wang H., Malafa M., Suh N. Vitamin E and cancer prevention: studies with different forms of tocopherols and tocotrienols. Mol Carcinog. 2020; 59 (4): 365–89. DOI: https://doi.org/10.1002/mc.23160

36. Jiang Q. Natural forms of vitamin E and metabolites–regulation of cancer cell death and underlying mechanisms. IUBMB Life. 2019; 71 (4): 495–506. DOI: https://doi.org/10.1002/iub.1978

37. Hemilä H. Vitamin E and mortality in male smokers of the ATBC Study: implications for nutritional recommendations. Front Nutr. 2020; 7: 36. DOI: https://doi.org/10.3389/fnut.2020.00036

38. Redzic S., Gupta V. Niacin deficiency; 2021. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. PMID: 32491660.

39. Eisemann T., Pascal J.M. Poly(ADP-ribose) polymerase enzymes and the maintenance of genome integrity. Cell Mol Life Sci. 2020; 77 (1): 19–33. DOI: https://doi.org/10.1007/s00018-019-03366-0

40. Xie N., Zhang L., Gao W., Huang C., Huber P.E., Zhou X., et al. NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct Target Ther. 2020; 5 (1): 227. DOI: https://doi.org/10.1038/s41392-020-00311-7

41. Dani N., Mayo E., Stilla A., Marchegiani A., Di Paola S., Corda D., Di Girolamo M. Mono-ADP-ribosylation of the G protein betagamma dimer is modulated by hormones and inhibited by Arf6. J Biol Chem. 2011; 286 (8): 5995–6005. DOI: https://doi.org/10.1074/jbc.M110.112466

42. Kirkland J.B. Niacin status and genomic instability in bone marrow cells; mechanisms favoring the progression of leukemogenesis. Subcell Biochem. 2012; 56: 21–36. DOI: https://doi.org/10.1007/978-94-007-2199-9_2

43. Oei S.L., Keil C., Ziegler M. Poly(ADP-ribosylation) and genomic stability. Biochem Cell Biol. 2005; 83 (3): 263–9. DOI: https://doi.org/10.1139/o05-039

44. Wang T., Wang Y., Liu L., Jiang Z., Li X., Tong R., et al. Research progress on sirtuins family members and cell senescence. Eur J Med Chem. 2020; 193: 112207. DOI: https://doi.org/10.1016/j.ejmech.2020.112207

45. Nikas I.P., Paschou S.A., Ryu H.S. The role of nicotinamide in cancer chemoprevention and therapy. Biomolecules. 2020; 10 (3): 477. DOI: https://doi.org/10.3390/biom10030477

46. Wohlrab J., Kreft D. Niacinamide – mechanisms of action and its topical use in dermatology. Skin Pharmacol Physiol. 2014; 27 (6): 311–5. DOI: https://doi.org/10.1159/000359974

47. Mascolo E., Vernì F. Vitamin B6 and diabetes: relationship and molecular mechanisms. Int J Mol Sci. 2020; 21 (10): 3669. DOI: https://doi.org/10.3390/ijms21103669

48. Bird R.P. The emerging role of vitamin B6 in inflammation and carcinogenesis. Adv Food Nutr Res. 2018; 83: 151–94. DOI: https://doi.org/10.1016/bs.afnr.2017.11.004

49. Moldogazieva N.T., Mokhosoev I.M., Mel’nikova T.I., Porozov Yu.B., Terentiev A.A. Oxidative stress and advanced lipoxidation and glycation end products (ALEs and AGEs) in aging and age-related diseases. Oxid Med Cell Longev. 2019; 2019: 3085756. DOI: https://doi.org/10.1155/2019/3085756

50. Tully D.B., Allgood V.E., Cidlowski J.A. Modulation of steroid receptor-mediated gene expression by vitamin B6. FASEB J. 1994; 8(3): 343–9. PMID: 8143940.

51. Merigliano C., Mascolo E., Burla R., Saggio I., Vernì F. The relationship between vitamin B6, diabetes and cancer. Front Genet. 2018; 9: 388. DOI: https://doi.org/10.3389/fgene.2018.00388

52. Ueland P.M., McCann A., Midttun Ø., Ulvik A. Inflammation, vitamin B6 and related pathways. Mol Aspects Med. 2017; 53: 10–27. DOI: https://doi.org/10.1016/j.mam.2016.08.001

53. Hansen M.F., Jensen S.Ø., Füchtbauer E.M., Martensen P.M. High folic acid diet enhances tumour growth in PyMT-induced breast cancer. Br J Cancer. 2017; 116 (6): 752–61. DOI: https://doi.org/10.1038/bjc.2017.11

54. Crott J.W., Liu Z., Keyes M.K., Choi S.W., Jang H., Moyer M.P., Mason J.B. Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines. J Nutr Biochem. 2008; 19 (5): 328–35. DOI: https://doi.org/10.1016/j.jnutbio.2007.05.003

55. Kim Y.-In. Folate, colorectal carcinogenesis, and DNA methylation: Lessons from animal studies. Environ Mol Mutagen. 2004; 44 (1): 10–25. DOI: https://doi.org/10.1002/em.20025

56. Kuo C.S., Lin C.Y., Wu M.Y., Lu C.L., Huang R.F. Relationship between folate status and tumour progression in patients with hepatocellular carcinoma. Br J Nutr. 2008; 100 (03): 596–602. DOI: https://doi.org/10.1017/S0007114508911557

57. Tomaszewski J.J., Cummings J.L., Parwani A.V., Dhir R., Mason J.B., Nelson J.B., et al. Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate. Prostate. 2011; 71 (12): 1287–93. DOI: https://doi.org/10.1002/pros.21346

58. Tu H., Dinney C.P., Ye Y., Grossman H.B., Lerner S.P., Wu X. Is folic acid safe for non–muscle-invasive bladder cancer patients? An evidence-based cohort study. Am J Clin Nutr. 2018; 107 (2): 208–16. DOI: https://doi.org/10.1093/ajcn/nqx019

59. Larsson S.C., Giovannucci E., Wolk A. Dietary folate intake and incidence of ovarian cancer: the Swedish Mammography Cohort. J Natl Cancer Inst. 2004; 96 (5): 396–402. DOI: https://doi.org/10.1093/jnci/djh061

60. Partearroyo T., Úbeda N., Montero A., Achón M., Varela-M.G. Vitamin B12 and folic acid imbalance modifies NK cytotoxicity, lymphocytes B and lymphoprolipheration in aged rats. Nutrients. 2013; 5 (12): 4836–48. DOI: https://doi.org/10.3390/nu5124836

61. Lin C.Y., Kuo C.S., Lu C.L., Wu M.Y., Huang R.F.S. Elevated serum vitamin B12 levels in association with tumor markers as the prognostic factors predictive for poor survival in patients with hepatocellular carcinoma. Nutr Cancer. 2010; 62 (2): 190–7. DOI: https://doi.org/10.1080/01635580903305334

62. Collin S.M., Metcalfe C., Refsum H., Lewis S.J., Zuccolo L., Smith G.D., et al. Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2010; 19 (6): 1632–42. DOI: https://doi.org/10.1158/1055-9965.EPI-10-0180

63. Fanidi A., Carreras-Torres R., Larose T.L., Yuan J.M., Stevens V.L., Weinstein S.J., et al. Is high vitamin B12 status a cause of lung cancer? Int J Cancer. 2019; 145 (6): 1499–503. DOI: https://doi.org/10.1002/ijc.32033

64. Said H.M. Biotin: biochemical, physiological and clinical aspects. Subcell Biochem. 2012; 56: 1–19. DOI: https://doi.org/10.1007/978-94-007-2199-9_1

65. McMahon R.J. Biotin in metabolism and molecular biology. Ann Rev Nutr. 2002; 22: 221–39. DOI: https://doi.org/10.1146/annurev.nutr.22.121101.112819

66. Sternicki L.M., Wegener K.L., Bruning J.B., Booker G.W., Polyak S.W. Mechanisms governing precise protein biotinylation. Trends Biochem Sci. 2017; 42 (5): 383–94. DOI: https://doi.org/10.1016/j.tibs.2017.02.001

67. Griffin J.B., Zempleni J. Biotin deficiency stimulates survival pathways in human lymphoma cells exposed to antineoplastic drugs. J Nutr Biochem. 2005; 16 (2): 96–103. DOI: https://doi.org/10.1016/j.jnutbio.2004.10.004

68. Hollenbeck C.B. An introduction to the nutrition and metabolism of choline. Cent Nerv Syst Agents Med Chem. 2012; 12 (2): 100–13. DOI: https://doi.org/10.2174/187152412800792689

69. Ueland P.M. Choline and betaine in health and disease. J Inherit Metab Dis. 2011; 34 (1): 3–15. DOI: https://doi.org/10.1007/s10545-010-9088-4

70. Zeisel S.H. Choline phospholipids: signal transduction and carcinogenesis. FASEB J. 1993; 7 (6): 551–7. DOI: https://doi.org/10.1096/fasebj.7.6.8472893

71. Ohanian J., Ohanian V. Sphingolipids in mammalian cell signalling. Cell Mol Life Sci. 2001; 58 (14): 2053–68. DOI: https://doi.org/10.1007/PL00000836

72. Zeisel S. Choline, other methyl-donors and epigenetics. Nutrients. 2017; 9 (5): 445. DOI: https://doi.org/10.3390/nu9050445

73. Glunde K., Penet M.F., Jiang L., Jacobs M.A., Bhujwalla Z.M. Choline metabolism-based molecular diagnosis of cancer: an update. Expert Rev Mol Diagn. 2015; 15 (6): 735–47. DOI: https://doi.org/10.1586/14737159.2015.1039515

74. Corbin K.D., Zeisel S.H. Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression. Curr Opin Gastroenterol. 2012; 28 (2): 159–65. DOI: https://doi.org/10.1097/MOG.0b013e32834e7b4b

75. Cho E., Holmes M.D., Hankinson S.E., Willett W.C. Choline and betaine intake and risk of breast cancer among post-menopausal women. Br J Cancer. 2010; 102 (3): 489–94. DOI: https://doi.org/10.1038/sj.bjc.6605510

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