Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms of combined action of different chemopreventive dietary compounds

A review

  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Consumption of fruits and vegetables has generally been associated with a decrease in cancer incidence and cardiovascular disease. Over the years, numerous bioactive compounds have been identified that contribute to these beneficial health effects. More recently, evidence is emerging that specific combinations of phytochemicals may be far more effective in protecting against cancer than isolated compounds. Combinatorial effects have been observed where any one of the single agents is inactive. Apart from interactions among dietary micronutrients, drug–phytochemical interactions have also been observed, indicating possibilities for improved cancer therapeutic strategies. Our understanding of the molecular mechanisms underlying such synergistic effects is still limited, but it appears that different combinations of complementary modes of actions are involved. In this review, we discuss the molecular mechanisms that are likely to be involved in cancer chemoprevention and summarize the most important findings of those studies that report synergistic chemopreventive effects of dietary compounds.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Anzano MA, Byers SW, Smith JM, Peer CW, Mullen LT, Brown CC, Roberts AB, Sporn MB (1994) Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. Cancer Res 54:4614–4617

    CAS  Google Scholar 

  2. Anzano MA, Peer CW, Smith JM, Mullen LT, Shrader MW, Logsdon DL, Driver CL, Brown CC, Roberts AB, Sporn MB (1996) Chemoprevention of mammary carcinogenesis in the rat: combined use of raloxifene and 9-cis-retinoic acid. J Natl Cancer Inst 88:122–125

    Article  Google Scholar 

  3. Balasubramanian S, Eckert RL (2004) Green tea polyphenol and curcumin inversely regulate human involucrin promoter activity via opposing effects on CCAAT/enhancer-binding protein function. J Biol Chem 279:24007–24014

    Article  CAS  Google Scholar 

  4. Bianchini F, Vainio H (2004) Isothiocyanates in cancer prevention. Drug Metab Rev 36:655–667

    Article  CAS  Google Scholar 

  5. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, Yang CS, Zheng SF, Gail M, Li GY (1993) Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 85:1483–1492

    Article  CAS  Google Scholar 

  6. Bowry VW, Ingold KU, Stocker R (1992) Vitamin E in human low-density lipoprotein. When and how this antioxidant becomes a pro-oxidant. Biochem J 288:341–344

    CAS  Google Scholar 

  7. van Breda SG, van Agen E, van Sanden S, Burzykowski T, Kienhuis AS, Kleinjans JC, van Delft JH (2005) Vegetables affect the expression of genes involved in anticarcinogenic processes in the colonic mucosa of C57BL/6 female mice. J Nutr 135:1879–1888

    Google Scholar 

  8. van Breda SG, van Agen E, van Sanden S, Burzykowski T, Kleinjans JC, van Delft JH (2005) Vegetables affect the expression of genes involved in carcinogenic and anticarcinogenic processes in the lungs of female C57BL/6 mice. J Nutr 135:2546–2552

    Google Scholar 

  9. van Breda SG, de Kok TM, van Delft JH (2007) Mechanisms of colorectal and lung cancer prevention by vegetables: a genomic approach J. Nutr Biochem (in press)

  10. Brusselmans K, Vrolix R, Verhoeven, Swinnen JV (2005) Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J Biol Chem 280:5636–5645

  11. Cai H, Al-Fayez M, Tunstall RG, Platton S, Greaves P, Steward WP, Gescher AJ (2005) The rice bran constituent tricin potently inhibits cyclooxygenase enzymes and interferes with intestinal carcinogenesis in APCmin mice. Mol Cancer Ther 4:1287–92

    Article  CAS  Google Scholar 

  12. Cai H, Hudson EA, Verschoyle RD, Greaves P, Manson MM, Steward WP (2004) Growth inhibitory and cell-cycle arresting properties of the rice bran constituent tricin in human-derived breast cancer cells in vitro and in nude mice in vivo. Br J Cancer 91:1364–1371

    Article  CAS  Google Scholar 

  13. Chemoprevention Working Group (1999) Prevention of cancer in the next millennium: Report of the Chemoprevention Working Group to the American Association for Cancer Research. Cancer Res 59:4743–4758

    Google Scholar 

  14. Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP (2005) Dietary flavonoids as proteosome inhibitors in human leukemia cells. Biochem Pharmacol 69:1421–1432

    Article  CAS  Google Scholar 

  15. De Beer D (2002) The antioxidant activity of South African wines in different test systems as affected by cultivar and aging. M.Sc thesis, Stellenbosch University, Stellenbosch, South Africa

  16. De Beer D, Joubert E, Marais J, Manley M (2006) Unravelling the total antioxidant capacity of pinotage wines: contribution of phenolic compounds. J Agric Food Chem 54:2897–2905

    Article  CAS  Google Scholar 

  17. Denison MS, Whitlock JP Jr (1995) Xenobiotic-inducible transcription of cytochrome P450 genes. J Biol Chem 270:18175–18178

    Article  CAS  Google Scholar 

  18. Duraj J, Zazrivcova K, Bodo J, Sulikova M, Sedlak J (2005) Flavonoid quercetin, but not apigenin or luteolin, induced apoptosis in human myeloid leukemia cells and their resistant variants. Neoplasma 52:273–279

    CAS  Google Scholar 

  19. Duthie SJ, Collins AR, Duthie GG, Dodson VL (1997) Quercetin and myricetin protect against hydrogen peroxide-induced DNA damage (strand breaks and oxidised pyrimidines) in human lymphocytes. Mut Res Gen Toxicol Environ Mutagenesis 393:223–231

    Article  CAS  Google Scholar 

  20. Eckert RL, Crish JF, Efimova T, Balasubramanian S (2006) Opposing action of curcumin and green tea polyphenol in human keratinocytes. Mol Nutr Food Res 50:123–129

    Article  CAS  Google Scholar 

  21. Fang MZ, Chen D, Sun Y, Christman JK, Yang CS (2005) Reversal of hypermethylation and reactivation of p16 ink4a, RARβ and MGMT genes by genistein and other isoflavones from soy. Clin Cancer Res 11:7033–17041

    Article  CAS  Google Scholar 

  22. Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H et al (2003) Tea polyphenol (−) -epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 63:7563–7570

    CAS  Google Scholar 

  23. Fenton JI, Hord NG (2004) Flavonoids promote cell migration in nontumorigenic colon epithelial cells differing in APC genotype: implications of matrix metalloproteinase activity. Nutr Cancer 48:182–188

    Article  CAS  Google Scholar 

  24. Fowke JH (2007) Head and neck cancer: a case for inhibition by isothiocyanates and indoles from cruciferous vegetables. Eur J Cancer Prev 16:348–356

    Article  CAS  Google Scholar 

  25. Franceschi S, Parpinel M, La Vecchia C, Favero A, Talamini R, Negri E (1998) Role of different types of vegetables and fruit in the prevention of cancer of the colon, rectum and breast. Epidemiology 9:338–341

    Article  CAS  Google Scholar 

  26. Geenwald P (2004) Clinical trials in cancer prevention: current results and perspectives for the future. J Nutr 134:350S–3512S

    Google Scholar 

  27. Gerhauser C, Alt A, Heiss E, Gamal-Eldeen A, Klimo K, Knauft J, Neumann I, Scherf HR, Frank N, Bartsch H, Becker H (2002) Cancer preventive activity of xanthohumol, a natural product derived from hop. Mol Cancer Ther 1:959–969

    CAS  Google Scholar 

  28. Gonzalez CA, Pera G, Agudo A, Bueno-de-Mesquita HB, Ceroti M et al (2006) Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EUGAST). Int J Cancer 118:2559–2566

    Article  CAS  Google Scholar 

  29. Gorelik S, Lapidot T, Shaham I, Granit R, Ligumsky M, Kohen R, Kanner J (2005) Lipid peroxidation and coupled vitamin oxidation in simulated and human gastric fluid inhibited by dietary polyphenols: health implications. J Agric Food Chem 53:3397–3402

    Article  CAS  Google Scholar 

  30. Hemalswarya S, Doble M (2006) Potential synergism of natural products in the treatment of cancer. Phytother Res 20:239–249

    Article  CAS  Google Scholar 

  31. Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R (1996) Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 334:1145–1149

    Article  CAS  Google Scholar 

  32. Hoogenboom R (2002) The combined use of the CALUX bioassay and the HRGC/HRMS method for the detection of novel dioxin sources and new dioxin-like compounds. Environ Sci Pollut Res Int 9:304–306

    Article  Google Scholar 

  33. Horie N, Hirabayashi N, Takahashi Y, Miyauchi Y, Taguchi H, Takeishi K (2005) Synergistic effect of green tea catechins on cell growth and apoptosis induction in gastric carcinoma cells. Biol Pharm Bull 28:574–579

    Article  CAS  Google Scholar 

  34. Howells LM, Moiseeva EP, Neal CP, Foreman BE, Andreadi CK, Sun Y, Manson MM (2007) Predicting the physiological relevance of in vitro cancer preventive activities of phytochemicals. Acta Pharmacol Sin 28:1273–1304

    Article  CAS  Google Scholar 

  35. Huang YT, Lee LT, Lee PPH, Lin YS, Lee MT (2005) Targeting of focal adhesion kinase by flavonoids and small interfering RNAs reduces tumor cell migration ability. Anticancer Res 25:2017–2025

    CAS  Google Scholar 

  36. Jansen MC, Bueno-de-Mesquita HB, Feskens EJ, Streppel MT, Kok FJ, Kromhout D (2004) Quantity and variety of fruit and vegetable consumption and cancer risk. Nutr Cancer 48:142–148

    Article  Google Scholar 

  37. Jones EL, Zhao MJ, Stevenson MA, Calderwood SK (2004) The 70 kilodalton heat shock protein is an inhibitor of apoptosis in prostate cancer. Int J Hyperthermia 20:835–849

    Article  CAS  Google Scholar 

  38. Jørgenson LC, Madsen HL, Dragsted L, Skibsted LH (1999) Regeneration of phenolic antioxidants from phenoxyl radicals: an ESR and electrochemical study of antioxidant hierarchy. Free Radical Res 30:207–220

    Article  Google Scholar 

  39. Khafif A, Schantz SP, Chou TC, Edelstein D, Sacks PG (1998) Quantitation of chemopreventive synergism between (−)-epigallocatechin-3-gallate and curcumin in normal, premalignant and malignant oral epithelial cells. Carcinogenesis 19:419–424

    Article  CAS  Google Scholar 

  40. Kim WK, Bang MH, Kim ES, Kang NE, Jung KC, Cho HJ, Park JH (2005) Quercetin decreases the expression of ErbB2 and ErbB3 proteins in HT-29 human colon cancer cells. J Nutr Biochem 16:155–162

    Article  CAS  Google Scholar 

  41. Knekt P, Jarvinen R, Seppanen R, Hellövaara M, Teppo L, Pukkala E, Aromaa A (1997) Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am J Epidemiol 146:223–230

    CAS  Google Scholar 

  42. Kuo PC, Liu HF, Chao JI (2004) Survivin and p53 modulate quercetin-induced cell growth inhibition and apoptosis in human lung carcinoma cells. J Biol Chem 279:55875–55885

    Article  CAS  Google Scholar 

  43. Limtrakul P, Khantamat O, Pintha K (2005) Inhibition of P-glycoprotein function and expression by kaempferol and quercetin. J Chemother 17:86–95

    CAS  Google Scholar 

  44. Liu RH (2004) Potential synergy of phytochemicals in cancer prevention: mechanism of action. J Nutr 134:3479S–3485S

    CAS  Google Scholar 

  45. Liu Z, Ma LP, Zhou B, Yang L, Liu ZL (2000) Antioxidative effects of green tea polyphenols on free radical initiated and photosensitized peroxidation of human low density lipoprotein. Chem Phys Lipids 106:53–63

    Article  CAS  Google Scholar 

  46. Lyn-Cook BD, Rogers T, Yan Y, Blann EB, Kadlubar FF, Hammons GJ (1999) Chemopreventive effects of tea extracts and various components on human pancreatic and prostate tumor cells in vitro. Nutr Cancer 35:80–86

    Article  CAS  Google Scholar 

  47. Manson MM (2003) Cancer prevention—the potential for diet to modulate molecular signalling. Trends Mol Med 9:11–18

    Article  CAS  Google Scholar 

  48. Morre DJ, Morre DM (2003) Cell surface NADH oxidases (ECTO-NOX proteins) with roles in cancer, cellular time-keeping, growth, aging and neurodegenerative diseases. Free Radic Res 37:795–808

    Article  CAS  Google Scholar 

  49. Morre DM, Morre DJ (2006) Anticancer activity of grape and grape skin extracts alone and combined with green tea infusions. Cancer Lett 238:202–209

    Article  CAS  Google Scholar 

  50. O’Leary KA, de Pascual-Tereasa S, Bao YP, O’Brien NM, Williamson G (2004) Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription. Mutat Res 551:245–254

    CAS  Google Scholar 

  51. Ohigashi H, Murakami A (2004) Cancer prevention with food factors: alone and in combination. Biofactors 22(1–4):49–55

    CAS  Google Scholar 

  52. Ohishi T, Kishimoto Y, Miura N, Shiota G, Kohri T, Hara Y, Hasegawa J, Isemura M (2002) Synergistic effects of (−)-epigallocatechin gallate with sulindac against colon carcinogenesis of rats treated with azoxymethane. Cancer Let 177:49–56

    Article  CAS  Google Scholar 

  53. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Barnhart S, Hammar S (1996) Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334:1150–1155

    Article  CAS  Google Scholar 

  54. Pappa G, Strathmann J, Löwinger M, Bartsch H, Gerhäuser C (2007) Quantitative combination effects between sulforaphane and 3′3′-diindolylmethane on proliferation of human colon cancer cells in vitro. Carcinogenesis 28:1477–1477

    Article  CAS  Google Scholar 

  55. Park CH, Chang JY, Hahm ER, Park S, Kim HK, Yang CH (2005) Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells. Biochem Biophys Res Comm 328:227–234

    Article  CAS  Google Scholar 

  56. Sarkar FH, Li Y (2006) Using chemopreventive agents to enhance the efficacy of cancer therapy. Cancer Res 66:3347–3350

    Article  CAS  Google Scholar 

  57. Sarkar FH, Li Y (2007) Targeting multiple signal pathways by chemopreventive agents for cancer prevention and therapy. Acta Pharmacol Sin 28:1305–1315

    Article  CAS  Google Scholar 

  58. Suganuma M, Okabe S, Kai Y, Sueoka N, Sueoka E, Fujiki H (1999) Synergistic effects of (−)-epigallocatechin gallate with (−)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9. Cancer Res 59:44–47

    CAS  Google Scholar 

  59. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (1994) The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330:1029–1035

    Article  Google Scholar 

  60. Vainio H, Weiderpass E (2006) Fruit and vegetables in cancer prevention. Nutr Cancer 54:111–142

    Article  CAS  Google Scholar 

  61. Volate SR, Davenport DM, Muga SJ, Wargovich MJ (2005) Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin). Carcinogenesis 26:1450–1456

    Article  CAS  Google Scholar 

  62. Waite KA, Sinden MR, Eng C (2005) Phytoestrogen exposure elevates PTEN levels. Human Mol Genet 14:1457–1463

    Article  CAS  Google Scholar 

  63. Wallig MA Heinz-Taheny KM, Donna L. Epps DL, Gos T (2005) Synergy among phytochemicals within crucifers: does it translate into chemoprotection? J Nutr 135:2972S–2977S

    Google Scholar 

  64. Wang WQ, VanAlstyne PC, Irons KA, Chen S, Stewart JW, Birt DR (2004) Individual and interactive effects of apigenin analogs on G2/M cell cycle arrest in human colon carcinoma cell lines. Nutr Cancer 48:106–114

    Article  CAS  Google Scholar 

  65. Williams SN, Pickwell GV, Quattrochi LC (2003) A combination of tea (Camellia senensis) catechins is required for optimal inhibition of induced CYP1A expression by green tea extract. J Agric Food Chem 51:6627–6634

    Article  CAS  Google Scholar 

  66. Williams SN, Shih H, Guenette DK, Brackney W, Denison MS, Pickwell GV, Quattrochi LC (2000) Comparative studies on the effects of green tea extracts and individual tea catechins on human CYP1A gene expression. Chem Biol Interact 128:211–229

    Article  CAS  Google Scholar 

  67. Wilms L, Boots AW, de Boer VC, Maas LM, Pachen DM, Gottschalk RW, Ketelslegers HB, Godschalk RW, Haenen GR, van Schooten FJ, Kleinjans JC (2007) Impact of multiple genetic polymorphisms on effects of a four-week blueberry juice intervention on ex vivo induced lymphocytic DNA damage in human volunteers. Carcinogenesis (in press)

  68. Wilms LC, Hollman PCH, Boots AW, Kleinjans JCS (2005) Protection by quercitin and quercetin-rich fruit juice against induction of oxidative DNA damage and formation of BPDE–DNA adducts in human lymphocytes. Mut Res 582:155–162

    CAS  Google Scholar 

  69. World Cancer Research Fund/American Institute for Cancer Research (2007) Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington DC: AICR, 2007

  70. Wu CP, Calcagno SB, Hladky SB, Ambudkar SV, Barrand MA (2005) Modulatory effects of plant phenols on human multi-drug resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). Febs J 272:4725–4740

    Article  CAS  Google Scholar 

  71. Yuan HQ, Gong AY, Young CYF (2005) Involvement of transcription factor Sp1 in quercetin-mediated inhibitory effect on the androgen receptor in human prostate cancer cells. Carcinogenesis 26:793–801

    Article  CAS  Google Scholar 

  72. Zhang S, Qin CH, Safe SH (2003) Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell-context. Env Health Persp 111:1877–1882

    CAS  Google Scholar 

  73. Zhou B, Jia ZS, Chen ZH, Yang L, Wu LM, Liu ZL (2000) Synergistic antioxidant effect of green tea polyphenols with α-tocopherol on green radical initiated peroxidation of linoleic acid in micelles. J Chem Soc Perkin Trans 2:785–791

    Google Scholar 

  74. Zhou B, Wu LM, Yang L, Liu ZL (2005) Evidence for alpha-tocopherol regeneration reaction of green tea polyphenols in SDS micelles. Free Radic Biol Med 38:78–84

    Article  CAS  Google Scholar 

  75. Zhou JR, Yu L, Mai Z, Blackburn GL (2004) Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice. Int J Cancer 108:8–14

    Article  CAS  Google Scholar 

  76. Zhou JR, Yu L, Zhong Y, Blackburn GL (2003) Soy phytochemicals and tea bioactive components synergistically inhibit androgen-sensitive human prostate tumors in mice. J Nutr 133:516–521

    CAS  Google Scholar 

  77. Zhou JR, Yu L, Zhong Y, Nassr RL, Franke AA, Gaston SM, Blackburn GL (2002) Inhibition of orthotopic growth and metastasis of androgen-sensitive human prostate tumors in mice by bioactive soybean components. Prostate 53:143–153

    Article  CAS  Google Scholar 

Download references

Conflict of Interest:

none.

Author information

Authors and Affiliations

  1. Department of Health Risk Analysis and Toxicology, University of Maastricht, Maastricht, The Netherlands

    Theo M. de Kok & Simone G. van Breda

  2. Cancer Biomarkers and Prevention Group, University of Leicester, Leicester, UK

    Margaret M. Manson

Authors
  1. Theo M. de Kok
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simone G. van Breda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Margaret M. Manson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theo M. de Kok.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Kok, T.M., van Breda, S.G. & Manson, M.M. Mechanisms of combined action of different chemopreventive dietary compounds. Eur J Nutr 47 (Suppl 2), 51–59 (2008). https://doi.org/10.1007/s00394-008-2006-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-008-2006-y

Key words

Search

Navigation