Folate in Skin Cancer Prevention

  • J.D. Williams
  • Elaine L. Jacobson
  • H. Kim
  • M. Kim
  • M.K. JacobsonEmail author
Part of the Subcellular Biochemistry book series (SCBI, volume 56)


Skin, the largest, most exposed organ of the body, provides a protective interface between humans and the environment. One of its primary roles is protection against exposure to sunlight, a major source of skin damage where the UV radiation (UVR) component functions as a complete carcinogen. Melanin pigmentation and the evolution of dark skin is an adaptive protective mechanism against high levels of UVR exposure. Recently, the hypothesis that skin pigmentation balances folate preservation and Vitamin D production has emerged. Both micronutrients are essential for reproductive success. Photodegradation of bioactive folates suggests a mechanism for the increased tendency of populations of low melanin pigmentation residing in areas of high UV exposure to develop skin cancers. Folate is proposed as a cancer prevention target for its role in providing precursors for DNA repair and replication, as well as its ability to promote genomic integrity through the generation of methyl groups needed for control of gene expression. The cancer prevention potential of folate has been demonstrated by large-scale epidemiological and nutritional studies indicating that decreased folate status increases the risk of developing certain cancers. While folate deficiency has been extensively documented by analysis of human plasma, folate status within skin has not been widely investigated. Nevertheless, inefficient delivery of micronutrients to skin and photolysis of folate argue that documented folate deficiencies will be present if not exacerbated in skin. Our studies indicate a critical role for folate in skin and the potential to protect sun exposed skin by effective topical delivery as a strategy for cancer prevention.


Cancer prevention DNA repair Folate Folic acid Skin Topical delivery strategy UV light 



The research described herein was supported in part by the National Institutes of Health and Niadyne, Inc. ELJ and MKJ are principles in Niadyne, Inc. and conflict of interest management is conducted by the University of Arizona Board of Regents.


  1. Agar NS, Halliday GM, Barnetson RS, Ananthaswamy HN, Wheeler M, Jones AM (2004) The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: A role for UVA in human skin carcinogenesis. Proc Natl Acad Sci USA 101:4954–4959PubMedCrossRefGoogle Scholar
  2. Ames BN (2001) DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res 475:7–20PubMedCrossRefGoogle Scholar
  3. Anderson BD, Higuchi WI, Raykar PV (1998) Heterogeneity effects on permeability–partition coefficient relationships in human stratum corneum. Pharm Res 5:566–573CrossRefGoogle Scholar
  4. Blakley RL (1969) The biochemistry of folic acid and related pteridines. In: Tatum EL (ed) Frontiers of biology, vol 13. North Holland Publishing Company, New YorkGoogle Scholar
  5. Branda RF, Eaton JW (1978) Skin color and nutrient photolysis: An evolutionary hypothesis. Science 201:625–626.PubMedCrossRefGoogle Scholar
  6. Brattstrom L, Wilcken DE (2000) Homocysteine and cardiovascular disease: Cause or effect? Am J Clin Nutr 72:315–323PubMedGoogle Scholar
  7. Butterworth CE Jr (1993) Folate status, women’s health, pregnancy outcome, and cancer. J Am Coll Nutr 12:438–441PubMedGoogle Scholar
  8. Chen AT, Reidy JA, Annest JL, Welty TK, Zhou HG (1989) Increased chromosome fragility as a consequence of blood folate levels, smoking status, and coffee consumption. Environ Mol Mutagen 13:319–324PubMedCrossRefGoogle Scholar
  9. Choi SW, Mason JB (2000) Folate and carcinogenesis: An integrated scheme. J Nutr 130:129–132PubMedGoogle Scholar
  10. Choi SW, Kim YI, Weitzel JN, Mason JB (1998) Folate depletion impairs DNA excision repair in the colon of the rat. Gut 43:93–99PubMedCrossRefGoogle Scholar
  11. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer Disease. Arch Neurol 55:1449–1455PubMedCrossRefGoogle Scholar
  12. Cohn BA (1998) The vital role of the skin in human natural history. Int J Dermatol 37:821–824PubMedCrossRefGoogle Scholar
  13. Dietrich M, Brown CJ, Block G (2005) The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the united states. J Am Coll Nutr 24:266–274PubMedGoogle Scholar
  14. Duthie SJ, Hawdon A (1998) DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB J 12:1491–1497PubMedGoogle Scholar
  15. Fang JY, Xiao SD, Zhu SS, Yuan JM, Qiu DK, Jiang SJ (1997) Relationship of plasma folic acid and status of DNA methylation in human gastric cancer. J Gastroenterol 32:171–175PubMedCrossRefGoogle Scholar
  16. Gambichler T, Bader A, Sauermann K, Altmeyer P, Hoffmann K (2001) Serum folate levels after UVA exposure: a two-group parallel randomised controlled trial. BMC Dermatol 1:8PubMedCrossRefGoogle Scholar
  17. Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH (1990) Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336:392–395PubMedCrossRefGoogle Scholar
  18. Goldsmith LA (1991) Physiology, biochemistry, and molecular biology of the skin, 2nd edn, 1 vols. vol. 1. Oxford University Press, New YorkGoogle Scholar
  19. Guenthner ST, Hurwitz RM, Buckel LJ, Gray HR (1999) Cutaneous squamous cell carcinomas consistently show histologic evidence of in situ changes: a clinicopathologic correlation. J Am Acad Dermatol 41:443–448PubMedCrossRefGoogle Scholar
  20. Heath CW Jr (1966) Cytogenetic observations in vitamin B12 and folate deficiency. Blood 27:800–815PubMedGoogle Scholar
  21. Herbert V, Larrabee AR, Buchanan JM (1962) Studies on the identification of a folate compound of human serum. J Clin Invest 41:1134–1138PubMedCrossRefGoogle Scholar
  22. Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, Pogribna M, Rozen R, James SJ (2000) Polymorphisms in genes involved in folate metabolism as maternal risk factors for down syndrome. Am J Hum Genet 67:623–630PubMedCrossRefGoogle Scholar
  23. Holick MF (2003) Vitamin D: a millenium perspective. J Cell Biochem 88:296–307PubMedCrossRefGoogle Scholar
  24. Holick MF, MacLaughlin JA, Doppelt SH (1981) Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science 211:590–593PubMedCrossRefGoogle Scholar
  25. Hurwitz RM, Monger LE (1995) Solar keratosis: an evolving squamous cell carcinoma. Benign or malignant? Dermatol Surg 21:184PubMedGoogle Scholar
  26. Jablonski NG (2004) The evolution of human skin and skin color. Annu Rev Anthropol 33:585-C-581CrossRefGoogle Scholar
  27. Jablonski NG, Chaplin G (2000) The evolution of human skin coloration. J Hum Evol 39:57–106PubMedCrossRefGoogle Scholar
  28. Jeffes EW 3rd, Tang EH (2000) Actinic keratosis. Current treatment options. Am J Clin Dermatol 1:167–179PubMedCrossRefGoogle Scholar
  29. Jimbow K, Quevedo WC Jr, Fitzpatrick TB, Szabo G (1976) Some aspects of melanin biology: 1950–1975. J Invest Dermatol 67:72–89PubMedCrossRefGoogle Scholar
  30. John Scott FRJF (2000) Folic acid and folates: the feasibility for nutritional enhancement in plant foods. J Sci Food Agric 80:795–824CrossRefGoogle Scholar
  31. Kamei T, Kohno T, Ohwada H, Takeuchi Y, Hayashi Y, Fukuma S (1993) Experimental study of the therapeutic effects of folate, vitamin A, and vitamin B12 on squamous metaplasia of the bronchial epithelium. Cancer 71:2477–2483PubMedCrossRefGoogle Scholar
  32. Karagas MR, Greenberg ER, Spencer SK, Stukel TA, Mott LA (1999) Increase in incidence rates of basal cell and squamous cell skin cancer in New Hampshire, USA. New Hampshire skin cancer study group. Int J Cancer 81:555–559PubMedCrossRefGoogle Scholar
  33. Kobayashi N, Nakagawa A, Muramatsu T, Yamashina Y, Shirai T, Hashimoto MW, Ishigaki Y, Lehman TA, Modali R, Boukamp P, Stanek J, Bennett WP, Welsh JA, Metcalf RA, Stampfer MJ, Lober BA, Lober CW, Accola J (2000) Actinic keratosis is squamous cell carcinoma. J Am Acad Dermatol 43:881–882Google Scholar
  34. Loomis WF (1967) Skin-pigment regulation of vitamin-D biosynthesis in man. Science 157:501–506PubMedCrossRefGoogle Scholar
  35. Lucock M (2000) Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab 71:121–138PubMedCrossRefGoogle Scholar
  36. Lucock M, Yates Z, Glanville T, Leeming R, Simpson N, Daskalakis I (2003) A critical role for B-vitamin nutrition in human developmental and evolutionary biology. Nutr Res 23:1463–1475CrossRefGoogle Scholar
  37. Madronich S, McKenzie RL, Bjorn LO, Caldwell MM (1998) Changes in biologically active ultraviolet radiation reaching the Earth’s surface. J Photochem Photobiol B 46:5–19PubMedCrossRefGoogle Scholar
  38. MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: Results of the medical research council vitamin study. Lancet 338:131–137CrossRefGoogle Scholar
  39. Nielsen KP, Lu Z, Juzenas P, Stamnes JJ, Stamnes K, Moan J (2004) Reflectance spectra of pigmented and nonpigmented skin in the UV spectral region. Photochem Photobiol 80:450–455PubMedGoogle Scholar
  40. Nielsen KP, Zhao L, Stamnes JJ, Stamnes K, Moan J (2006) The importance of the depth distribution of melanin in skin for DNA protection and other photobiological processes. J Photochem Photobiol B 82:194–198PubMedCrossRefGoogle Scholar
  41. Off MK, Steindal AE, Porojnicu AC, Juzeniene A, Vorobey A, Johnsson A, Moan J (2005) Ultraviolet photodegradation of folic acid. J Photochem Photobiol B 80:47–55PubMedCrossRefGoogle Scholar
  42. Ohnishi T, Mori T (1998) Supranuclear melanin caps reduce ultraviolet induced DNA photoproducts in human epidermis. J Invest Dermatol 110:806–810PubMedCrossRefGoogle Scholar
  43. Peng YM, Peng YS, Lin Y, Moon T, Baier M (1993) Micronutrient concentrations in paired skin and plasma of patients with actinic keratoses: effect of prolonged retinol supplementation. Cancer Epidemiol Biomarkers Prev 2:145–150PubMedGoogle Scholar
  44. Pentland AP, Schoggins JW, Scott GA, Khan KN, Han R (1999) Reduction of UV-induced skin tumors in hairless mice by selective cox-2 inhibition. Carcinogenesis 20:1939–1944PubMedCrossRefGoogle Scholar
  45. Post PW, Daniels F Jr, Binford RT Jr (1975) Cold injury and the evolution of “White” skin. Hum Biol 47:65–80.PubMedGoogle Scholar
  46. Rajkovic A, Catalano PM, Malinow MR (1997) Elevated homocyst(e)ine levels with preeclampsia. Obstet Gynecol 90:168–171PubMedCrossRefGoogle Scholar
  47. Roberts MS, Anderson RA, Swarbrick J, Moore DE (1978) The percutaneous absorption of phenolic compounds: the mechanism of diffusion across the stratum corneum. J Pharm Pharmacol 30:486–490PubMedCrossRefGoogle Scholar
  48. Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 96:12810–12815PubMedCrossRefGoogle Scholar
  49. Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M (1999) Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 8:513–518PubMedGoogle Scholar
  50. Stampfer MR, Fusenig N, Rogan EM et al (1993) P53 mutations in human immortalized epithelial cell lines. Carcinogenesis 14:833–839PubMedCrossRefGoogle Scholar
  51. Steindal AH, Porojnicu AC, Moan J (2006) Is the seasonal variation in cancer prognosis caused by sun-induced folate degradation? Med Hypotheses. Dec 29, EPub ahead of printGoogle Scholar
  52. Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, Albanes D (2001) Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. Am J Epidemiol 153:680–687PubMedCrossRefGoogle Scholar
  53. Szabo G, Gerald AB, Pathak MA, Fitzpatrick TB (1969) Racial differences in the fate of melanosomes in human epidermis. Nature 222:1081–1082PubMedCrossRefGoogle Scholar
  54. Taylor SC (2002) Skin of color: biology, structure, function, and implications for dermatologic disease. J Am Acad Dermatol 46:S41–S62PubMedCrossRefGoogle Scholar
  55. Thien KR, Blair JA, Leeming RJ, Cooke WT, Melikian V (1977) Serum folates in man. J Clin Pathol 30:438–448PubMedCrossRefGoogle Scholar
  56. Thody AJ, Higgins EM, Wakamatsu K, Ito S, Burchill SA, Marks JM (1991) Pheomelanin as well as eumelanin is present in human epidermis. J Invest Dermatol 97:340–344PubMedCrossRefGoogle Scholar
  57. Tsai R-S, El Tayar N, Carrupt P-A, Testa B (1992) Physicochemical properties and transport behaviour of piribedil: Considerations on its membrane-crossing potential. Int J Pharm 80:39–49CrossRefGoogle Scholar
  58. Ullrich SE (2002) Photoimmune suppression and photocarcinogenesis. Front Biosci 7:684–703CrossRefGoogle Scholar
  59. Weber H, Meyer-Trumpener K, Lippold BC (1994) Esters of naproxen as potential prodrugs for skin penetration. 2. Penetration behavior in excised mice skin. Arch Pharm 327:681–686CrossRefGoogle Scholar
  60. Wills L (1978) Nutrition classics. British Medical Journal 1:1059–64, 1931. Treatment of “Pernicious anaemia of pregnancy” and “Tropical anaemia” With special reference to yeast extract as a curative agent. By lucy wills. Nutr Rev 36:149–151CrossRefGoogle Scholar
  61. Wondrak GT, Cervantes-Laurean D, Roberts MJ, Qasem JG, Kim M, Jacobson EL, Jacobson MK (2002a) Identification of alpha-dicarbonyl scavengers for cellular protection against carbonyl stress. Biochem Pharmacol 63:361–373PubMedCrossRefGoogle Scholar
  62. Wondrak GT, Roberts MJ, Jacobson MK, Jacobson EL (2002b) Photosensitized growth inhibition of cultured human skin cells: Mechanism and suppression of oxidative stress from solar irradiation of glycated proteins. J Invest Dermatol 119:489–498PubMedCrossRefGoogle Scholar
  63. Wondrak GT, Roberts MJ, Cervantes-Laurean D, Jacobson MK, Jacobson EL (2003) Proteins of the extracellular matrix are sensitizers of photo-oxidative stress in human skin cells. J Invest Dermatol 121:578–586PubMedCrossRefGoogle Scholar
  64. Wong WY, Merkus HM, Thomas CM, Menkveld R, Zielhuis GA, Steegers-Theunissen RP (2002) Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. Fertil Steril 77:491–498PubMedCrossRefGoogle Scholar
  65. Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, Speizer FE, Willett WC (1999) A prospective study of folate intake and the risk of breast cancer. JAMA 281:1632–1637PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • J.D. Williams
    • 1
    • 2
  • Elaine L. Jacobson
    • 1
    • 2
  • H. Kim
    • 1
    • 2
  • M. Kim
    • 1
    • 2
  • M.K. Jacobson
    • 1
    • 2
    Email author
  1. 1.Division of Medicinal Chemistry, Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer CenterUniversity of ArizonaTucsonUSA
  2. 2.Niadyne Development, Inc.TucsonUSA

Personalised recommendations