Skip to main content
SpringerLink
Log in

Cancer Prevention by Different Forms of Tocopherols

  • Chapter
  • First Online:
Natural Products in Cancer Prevention and Therapy

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 329))

Abstract

Many epidemiological studies have suggested that a low vitamin E nutritional status is associated with increased cancer risk. However, several recent large-scale human trials with high doses of α-tocopherol (α-T) have produced disappointing results. This points out the need for a better understanding of the biological activities of the different forms of tocopherols. Using a naturally occurring tocopherol mixture (γ-TmT) that is rich in γ-T, we demonstrated the inhibition of chemically induced lung, colon, and mammary cancer formation as well as the growth of xenograft tumors derived from human lung and prostate cancer cells. This broad anticancer activity of γ-TmT has been attributed mainly to the trapping of reactive oxygen and nitrogen species and inhibition of arachidonic acid metabolism. Activation of peroxisome proliferator-activated receptor γ (PPARγ) and the inhibition of estrogen signaling have also been observed in the inhibition of mammary cancer development. δ-T has been shown to be more active than γ-T in inhibiting the growth of human lung cancer cells in a xenograft tumor model and the development of aberrant crypt foci in azoxymethane-treated rats, whereas α-T is not effective in these models. The higher inhibitory activities of δ-T and γ-T (than α-T) are proposed to be due to their trapping of reactive nitrogen species and their capacity to generate side-chain degradation products, which retain the intact chromanol ring structure and could have cancer preventive activities.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Traber MG (2006) Vitamin E. In: Bowman BA, Russell RM (eds) Present knowledge in nutrition, 9th edn. ILSI Press, Washington, DC, pp 211–219

    Google Scholar 

  2. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN (1997) Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci USA 94:3217–3222

    Article  CAS  Google Scholar 

  3. Cooney RV, Franke AA, Harwood PJ, Hatch-Pigott V, Custer LJ, Mordan LJ (1993) Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alpha-tocopherol. Proc Natl Acad Sci USA 90:1771–1775

    Article  CAS  Google Scholar 

  4. Jiang Q, Lykkesfeldt J, Shigenaga MK, Shigeno ET, Christen S, Ames BN (2002) Gamma-tocopherol supplementation inhibits protein nitration and ascorbate oxidation in rats with inflammation. Free Radic Biol Med 33:1534–1542

    Article  CAS  Google Scholar 

  5. Patel A, Liebner F, Netscher T, Mereiter K, Rosenau T (2007) Vitamin E chemistry. Nitration of non-alpha-tocopherols: products and mechanistic considerations. J Org Chem 72:6504–6512

    Article  CAS  Google Scholar 

  6. U.S. (2005) Department of Commerce and U.S. Bureau of the Census. Fat and oils: production, consumption, and stocks 2004

    Google Scholar 

  7. Eitenmiller RR, Lee J (2004) Vitamin E: food chemistry, composition, and analysis. Marcel Dekker, New York

    Book  Google Scholar 

  8. Qian J, Morley S, Wilson K, Nava P, Atkinson J, Manor D (2005) Intracellular trafficking of vitamin E in hepatocytes: the role of tocopherol transfer protein. J Lipid Res 46:2072–2082

    Article  CAS  Google Scholar 

  9. Ju J, Picinich SC, Yang Z, Zhao Y, Suh N, Kong AN, Yang CS (2009) Cancer preventive activities of tocopherols and tocotrienols. Carcinogenesis 31:533–542

    Article  Google Scholar 

  10. Jiang Q, Christen S, Shigenaga MK, Ames BN (2001) Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 74:714–722

    CAS  Google Scholar 

  11. Campbell S, Stone W, Whaley S, Krishnan K (2003) Development of gamma-tocopherol as a colorectal cancer chemopreventive agent. Crit Rev Oncol Hematol 47:249–259

    Article  Google Scholar 

  12. Hensley K, Benaksas EJ, Bolli R, Comp P, Grammas P, Hamdheydari L, Mou S, Pye QN, Stoddard MF, Wallis G, Williamson KS, West M, Wechter WJ, Floyd RA (2004) New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine. Free Radic Biol Med 36:1–15

    Article  CAS  Google Scholar 

  13. Lu G, Xiao H, Li G, Chen K-Y, Hao J, Loy S, Yang CS (2010) γ-Tocopherols-rich mixture of tocopherols inhibits chemically-induced lung tumorigenesis in A/J mice and xenograft tumor growth. Carcinogenesis 31:687–694

    Article  CAS  Google Scholar 

  14. Li GX, Lee MJ, Liu AB, Yang Z, Lin Y, Shih WJ, Yang CS (2011) Delta-tocopherol is more active than alpha- or gamma-tocopherol in inhibiting lung tumorigenesis in vivo. Cancer Prev Res (Phila) 4:404–413

    Article  CAS  Google Scholar 

  15. Lambert JD, Lu G, Lee MJ, Hu J, Yang CS (2009) Inhibition of lung cancer growth in mice by dietary mixed tocopherols. Mol Nutr Food Res 53:1030–1035

    Article  CAS  Google Scholar 

  16. Ju J, Hao X, Lee MJ, Lambert JD, Lu G, Xiao H, Newmark HL, Yang CS (2009) A gamma-tocopherol-rich mixture of tocopherols inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice. Cancer Prev Res (Phila Pa) 2:143–152

    Article  CAS  Google Scholar 

  17. Lee HJ, Ju J, Paul S, So JY, DeCastro A, Smolarek AK, Lee MJ, Yang CS, Newmark HL, Suh N (2009) Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-g. Clin Cancer Res 15:4242–4249

    Article  CAS  Google Scholar 

  18. Suh N, Paul S, Lee HJ, Ji Y, Lee MJ, Yang CS, Reddy BS, Newmark HL (2007) Mixed tocopherols inhibit N-methyl-N-nitrosourea-induced mammary tumor growth in rats. Nutr Cancer 59:76–81

    Article  CAS  Google Scholar 

  19. Zheng X, Cui X-X, Khor TO, Huang Y, DiPaola RS, Goodin S, Lee M-J, Yang CS, Kong A-N, Conney AH (2012) Inhibitory effect of a γ-tocophenol-rich mixture of tocopherols on the formation and growth of LNCaP prostate tumors in immunodeficient mice. Cancers 3:3762–3772

    Google Scholar 

  20. Barve A, Khor TO, Nair S, Reuhl K, Suh N, Reddy B, Newmark H, Kong AN (2009) Gamma-tocopherol-enriched mixed tocopherol diet inhibits prostate carcinogenesis in TRAMP mice. Int J Cancer 124:1693–1699

    Article  CAS  Google Scholar 

  21. Woodson K, Albanes D, Tangrea JA, Rautalahti M, Virtamo J, Taylor PR (1999) Association between alcohol and lung cancer in the alpha-tocopherol, beta-carotene cancer prevention study in Finland. Cancer Causes Control 10:219–226

    Article  CAS  Google Scholar 

  22. Yong LC, Brown CC, Schatzkin A, Dresser CM, Slesinski MJ, Cox CS, Taylor PR (1997) Intake of vitamins E, C, and A and risk of lung cancer. The NHANES I epidemiologic followup study. First National Health and Nutrition Examination Survey. Am J Epidemiol 146:231–243

    Article  CAS  Google Scholar 

  23. Shibata A, Paganini-Hill A, Ross RK, Henderson BE (1992) Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: a prospective study. Br J Cancer 66:673–679

    Article  CAS  Google Scholar 

  24. Mahabir S, Schendel K, Dong YQ, Barrers SL, Spitz MR, Forman MR (2008) Dietary alpha-, beta-, gamma- and delta-tocopherols in lung cancer risk. Int J Cancer 123:1173–1180

    Article  CAS  Google Scholar 

  25. Bostick RM, Potter JD, McKenzie DR, Sellers TA, Kushi LH, Steinmetz KA, Folsom AR (1993) Reduced risk of colon cancer with high intake of vitamin E: the Iowa Women’s Health Study. Cancer Res 53:4230–4237

    CAS  Google Scholar 

  26. Ghadirian P, Lacroix A, Maisonneuve P, Perret C, Potvin C, Gravel D, Bernard D, Boyle P (1997) Nutritional factors and colon carcinoma: a case-control study involving French Canadians in Montreal, Quebec, Canada. Cancer 80:858–864

    Article  CAS  Google Scholar 

  27. White E, Shannon JS, Patterson RE (1997) Relationship between vitamin and calcium supplement use and colon cancer. Cancer Epidemiol Biomarkers Prev 6:769–774

    CAS  Google Scholar 

  28. Ingles SA, Bird CL, Shikany JM, Frankl HD, Lee ER, Haile RW (1998) Plasma tocopherol and prevalence of colorectal adenomas in a multiethnic population. Cancer Res 58:661–666

    CAS  Google Scholar 

  29. Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Morris JS, Comstock GW (2000) Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst 92:2018–2023

    Article  CAS  Google Scholar 

  30. Huang HY, Alberg AJ, Norkus EP, Hoffman SC, Comstock GW, Helzlsouer KJ (2003) Prospective study of antioxidant micronutrients in the blood and the risk of developing prostate cancer. Am J Epidemiol 157:335–344

    Article  Google Scholar 

  31. Wright ME, Weinstein SJ, Lawson KA, Albanes D, Subar AF, Dixon LB, Mouw T, Schatzkin A, Leitzmann MF (2007) Supplemental and dietary vitamin E intakes and risk of prostate cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev 16:1128–1135

    Article  CAS  Google Scholar 

  32. Smolarek AK, Suh N (2011) Chemopreventive activity of vitamin E in breast cancer: a focus on gamma-and delta-tocopherol. Nutrients 3:962–986

    Article  CAS  Google Scholar 

  33. Dorjgochoo T, Shrubsole MJ, Shu XO, Lu W, Ruan Z, Zheng Y, Cai H, Dai Q, Gu K, Gao YT, Zheng W (2008) Vitamin supplement use and risk for breast cancer: the Shanghai Breast Cancer Study. Breast Cancer Res Treat 111:269–278

    Article  CAS  Google Scholar 

  34. Nagel G, Linseisen J, van Gils CH, Peeters PH, Boutron-Ruault MC, Clavel-Chapelon F, Romieu I, Tjonneland A, Olsen A, Roswall N, Witt PM, Overvad K, Rohrmann S, Kaaks R, Drogan D, Boeing H, Trichopoulou A, Stratigakou V, Zylis D, Engeset D, Lund E, Skeie G, Berrino F, Grioni S, Mattiello A, Masala G, Tumino R, Zanetti R, Ros MM, Bueno-de-Mesquita HB, Ardanaz E, Sanchez MJ, Huerta JM, Amiano P, Rodriguez L, Manjer J, Wirfalt E, Lenner P, Hallmans G, Spencer EA, Key TJ, Bingham S, Khaw KT, Rinaldi S, Slimani N, Boffetta P, Gallo V, Norat T, Riboli E (2010) Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European prospective investigation into cancer and nutrition (EPIC). Breast Cancer Res Treat 119:753–765

    Article  CAS  Google Scholar 

  35. Schwenke DC (2002) Does lack of tocopherols and tocotrienols put women at increased risk of breast cancer? J Nutr Biochem 13:2–20

    Article  CAS  Google Scholar 

  36. Kimmick GG, Bell RA, Bostick RM (1997) Vitamin E and breast cancer: a review. Nutr Cancer 27:109–117

    Article  CAS  Google Scholar 

  37. Fulan H, Changxing J, Baina WY, Wencui Z, Chunqing L, Fan W, Dandan L, Dianjun S, Tong W, Da P, Yashuang Z (2011) Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression. Cancer Causes Control 22:1383–1396

    Article  Google Scholar 

  38. Lee IM, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE (2005) Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA 294:56–65

    Article  CAS  Google Scholar 

  39. Gaziano JM, Glynn RJ, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Sesso HD, Buring JE (2009) Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA 301:52–62

    Article  CAS  Google Scholar 

  40. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD 3rd, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz PA, Santella RM, Albanes D, Taylor PR, Probstfield JL, Jagpal TJ, Crowley JJ, Meyskens FL Jr, Baker LH, Coltman CA Jr (2009) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the selenium and vitamin E cancer prevention trial (SELECT). JAMA 301:39–51

    Article  CAS  Google Scholar 

  41. Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, Minasian LM, Ford LG, Parnes HL, Gaziano JM, Karp DD, Lieber MM, Walther PJ, Klotz L, Parsons JK, Chin JL, Darke AK, Lippman SM, Goodman GE, Meyskens FL Jr, Baker LH (2011) Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA 306:1549–1556

    Article  CAS  Google Scholar 

  42. Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, Hartman AM, Palmgren J, Freedman LS, Haapakoski J, Barrett MJ, Pietinen P, Malila N, Tala E, Liippo K, Salomaa ER, Tangrea JA, Teppo L, Askin FB, Taskinen E, Erozan Y, Greenwald P, Huttunen JK (1996) Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 88:1560–1570

    Article  CAS  Google Scholar 

  43. Weinstein SJ, Wright ME, Lawson KA, Snyder K, Mannisto S, Taylor PR, Virtamo J, Albanes D (2007) Serum and dietary vitamin E in relation to prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16:1253–1259

    Article  CAS  Google Scholar 

  44. Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, Albanes D, Taylor PR, Albert P (2003) Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA 290:476–485

    Article  CAS  Google Scholar 

  45. Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Maenpaa H, Teerenhovi L, Koss L, Virolainen M, Edwards BK (1998) Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 90:440–446

    Article  CAS  Google Scholar 

  46. Wagner KH, Kamal-Eldin A, Elmadfa I (2004) Gamma-tocopherol – an underestimated vitamin? Ann Nutr Metab 48:169–188

    Article  CAS  Google Scholar 

  47. Reiter E, Jiang Q, Christen S (2007) Anti-inflammatory properties of alpha- and gamma-tocopherol. Mol Aspects Med 28:668–691

    Article  CAS  Google Scholar 

  48. McNeil C (2011) Vitamin e and prostate cancer: research focus turns to biologic mechanisms. J Natl Cancer Inst 103:1731–1734

    Article  Google Scholar 

  49. Hagiwara A, Boonyaphiphat P, Tanaka H, Kawabe M, Tamano S, Kaneko H, Matsui M, Hirose M, Ito N, Shirai T (1999) Organ-dependent modifying effects of caffeine, and two naturally occurring antioxidants alpha-tocopherol and n-tritriacontane-16,18-dione, on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary and colonic carcinogenesis in female F344 rats. Jpn J Cancer Res 90:399–405

    Article  CAS  Google Scholar 

  50. Dias MF, Sousa E, Cabrita S, Patrício J, Oliveira CF (2000) Chemoprevention of DMBA-induced mammary tumors in rats by a combined regimen of alpha-tocopherol, selenium, and ascorbic acid. Breast J 6:14–19

    Article  CAS  Google Scholar 

  51. Hirose M, Nishikawa A, Shibutani M, Imai T, Shirai T (2002) Chemoprevention of heterocyclic amine-induced mammary carcinogenesis in rats. Environ Mol Mutagen 39:271–278

    Article  CAS  Google Scholar 

  52. Hirose M, Takahashi S, Ogawa K, Futakuchi M, Shirai T (1999) Phenolics: blocking agents for heterocyclic amine-induced carcinogenesis. Food Chem Toxicol 37:985–992

    Article  CAS  Google Scholar 

  53. Gould MN, Haag JD, Kennan WS, Tanner MA, Elson CE (1991) A comparison of tocopherol and tocotrienol for the chemoprevention of chemically induced rat mammary tumors. Am J Clin Nutr 53:1068S–1070S

    CAS  Google Scholar 

  54. Bonofiglio D, Gabriele S, Aquila S, Catalano S, Gentile M, Middea E, Giordano F, Ando S (2005) Estrogen receptor alpha binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor gamma signaling in breast cancer cells. Clin Cancer Res 11:6139–6147

    Article  CAS  Google Scholar 

  55. Yu W, Simmons-Menchaca M, Gapor A, Sanders BG, Kline K (1999) Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols. Nutr Cancer 33:26–32

    Article  Google Scholar 

  56. Yu W, Jia L, Wang P, Lawson KA, Simmons-Menchaca M, Park SK, Sun L, Sanders BG, Kline K (2008) In vitro and in vivo evaluation of anticancer actions of natural and synthetic vitamin E forms. Mol Nutr Food Res 52:447–456

    Article  CAS  Google Scholar 

  57. Yu W, Jia L, Park SK, Li J, Gopalan A, Simmons-Menchaca M, Sanders BG, Kline K (2009) Anticancer actions of natural and synthetic vitamin E forms: RRR-alpha-tocopherol blocks the anticancer actions of gamma-tocopherol. Mol Nutr Food Res 53:1573–1581

    Article  CAS  Google Scholar 

  58. Takahashi S, Takeshita K, Seeni A, Sugiura S, Tang M, Sato SY, Kuriyama H, Nakadate M, Abe K, Maeno Y, Nagao M, Shirai T (2009) Suppression of prostate cancer in a transgenic rat model via gamma-tocopherol activation of caspase signaling. Prostate 69:644–651

    Article  CAS  Google Scholar 

  59. Jiang Q, Yin X, Lill MA, Danielson ML, Freiser H, Huang J (2008) Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. Proc Natl Acad Sci USA 105:20464–20469

    Article  CAS  Google Scholar 

  60. Lin J, Cook NR, Albert C, Zaharris E, Gaziano JM, Van Denburgh M, Buring JE, Manson JE (2009) Vitamins C and E and beta carotene supplementation and cancer risk: a randomized controlled trial. J Natl Cancer Inst 101:14–23

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by US NIH grants CA122474, CA133021, CA141756, and John L. Colaizzi Chair endowment Fund. We acknowledge the contribution of Drs. Guangxun Li, Zhihong Yang, and Gang Lu for their contribution to research on this topic.

Author information

Authors and Affiliations

  1. Department of Chemical Biology, Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA

    Chung S. Yang & Nanjoo Suh

Authors
  1. Chung S. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nanjoo Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chung S. Yang .

Editor information

Editors and Affiliations

  1. College of Pharmacy, University of Hawaii, Rainbow Drive 34, Hilo, 96720, Hawaii, USA

    John M. Pezzuto

  2. Ernest Mario School of Pharmacy, Department of Chemical Biology, Rutgers University, Frelinghuysen Road 164, Piscataway, 08854-0789, New Jersey, USA

    Nanjoo Suh

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Yang, C.S., Suh, N. (2012). Cancer Prevention by Different Forms of Tocopherols. In: Pezzuto, J., Suh, N. (eds) Natural Products in Cancer Prevention and Therapy. Topics in Current Chemistry, vol 329. Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2012_345

Download citation

Publish with us

Policies and ethics

Search

Navigation