Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cancer chemoprevention: scientific promise, clinical uncertainty

Abstract

We review fundamental processes, such as mutation, oxidative stress, and inflammation that are critical for carcinogenesis and provide specific molecular targets for new chemopreventive agents. New information from molecular biology studies has identified such targets, including regulatory molecules such as Nrf2 (nuclear factor erythroid 2-related factor 2), epidermal growth factor receptor kinases, phosphatidylinositol 3-kinase, components of the Janus kinase–signal transducers and activators of transcription (JAK–STAT) pathway, nuclear factor-κB, and cyclin D. The development of new drugs for the control of these targets that are both safe and effective will be important for the future of cancer chemoprevention.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: For men and women in the US, younger than 85 years, death rates from heart disease have dropped markedly since 1975, while overall death rates from cancer have shown relatively little change.
Figure 2: A simplified diagram of the mechanisms that can activate the transcription factor, Nrf2.
Figure 3: The concept of 'health' needs to consider future events, not just the immediate present.

References

  1. 1

    Bishop JM (1997) Cancer: what should be done? Science 278: 995

    CAS  Article  Google Scholar 

  2. 2

    Fisher B et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P–1 study. J Natl Cancer Inst 98: 1371–1388

    Article  Google Scholar 

  3. 3

    Martino S et al. (2004) Continuing outcomes relevant to Evista: breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. J Natl Cancer Inst 96: 1751–1761

    CAS  Article  Google Scholar 

  4. 4

    Jemal A et al. (2005) Cancer statistics, 2005. CA Cancer J Clin 54: 10–30

    Article  Google Scholar 

  5. 5

    Sporn MB and Suh N (2002) Chemoprevention: an essential approach to controlling cancer. Nat Rev Cancer 2: 537–543

    CAS  Article  Google Scholar 

  6. 6

    Solomon SD et al. (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352: 1071–1080

    CAS  Article  Google Scholar 

  7. 7

    Bresalier RS et al. (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352: 1092–1102

    CAS  Article  Google Scholar 

  8. 8

    Hussain SP et al. (2003) Radical causes of cancer. Nat Rev Cancer 3: 276–285

    CAS  Article  Google Scholar 

  9. 9

    Marnett LJ (2000) Oxyradicals and DNA damage. Carcinogenesis 21: 361–370

    CAS  Article  Google Scholar 

  10. 10

    Sporn MB and Roberts AB (1986) Peptide growth factors and inflammation, tissue repair, and cancer. J Clin Invest 78: 329–332

    CAS  Article  Google Scholar 

  11. 11

    Coussens LM and Werb Z (2002) Inflammation and cancer. Nature 420: 860–867

    CAS  Article  Google Scholar 

  12. 12

    Balkwill F et al. (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7: 211–217

    CAS  Article  Google Scholar 

  13. 13

    Mann JR et al. (2005) Mechanisms of disease: inflammatory mediators and cancer prevention. Nat Clin Prac Oncol 2: 202–210

    CAS  Article  Google Scholar 

  14. 14

    Laird PW (2005) Cancer epigenetics. Hum Mol Genet 14: R65–R76

    CAS  Article  Google Scholar 

  15. 15

    Lund AH and van Lohuizen M (2004) Epigenetics and cancer. Genes Dev 18: 2315–2335

    CAS  Article  Google Scholar 

  16. 16

    Feinberg AP and Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4: 143–153

    CAS  Article  Google Scholar 

  17. 17

    Prestera T et al. (1993) The electrophile counterattack response: protection against neoplasia and toxicity. Adv Enzyme Regul 33: 291–296

    Article  Google Scholar 

  18. 18

    Kwak M-K et al. (2002) Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers. Mutat Res 555: 133–148

    Article  Google Scholar 

  19. 19

    Talalay P et al. (2003) Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis. Adv Enzyme Regul 43: 121–134

    CAS  Article  Google Scholar 

  20. 20

    Zhang Y and Gordon GB (2004) A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway. Mol Cancer Ther 3: 885–893

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Lee J-S and Surh Y-J (2005) Nrf2 as a novel molecular target for chemoprevention. Cancer Lett 224: 171–184

    CAS  Article  Google Scholar 

  22. 22

    Nguyen T et al. (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 43: 233–260

    CAS  Article  Google Scholar 

  23. 23

    Dinkova-Kostova A et al. (2005) Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 102: 4584–4589

    CAS  Article  Google Scholar 

  24. 24

    Liby K et al. (2005) The synthetic triterpenoids, CDDO and CDDO-Imidazolide are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res 65: 4789–4798

    CAS  Article  Google Scholar 

  25. 25

    Vodovotz Y (1997) Control of nitric oxide production by transforming growth factor-β1: mechanistic insights and potential relevance to human disease. Nitric Oxide 1: 3–17

    CAS  Article  Google Scholar 

  26. 26

    Ning W et al. (2002) TGF-β1 stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol 283: L1094–L1102

    CAS  Article  Google Scholar 

  27. 27

    Suh N et al. (2003) Synthetic triterpenoids enhance transforming growth factor-β/Smad signaling. Cancer Res 63: 1371–1376

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Otterbein LE et al. (2000) Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nature Med 6: 422–428

    CAS  Article  Google Scholar 

  29. 29

    Ryter SW et al. (2004) Carbon monoxide: to boldly go where NO has gone before. Sci STKE 2004: RE6

    PubMed  PubMed Central  Google Scholar 

  30. 30

    Poynter JN et al. (2005) Statins and the risk of colorectal cancer. N Engl J Med 352: 2184–2192

    CAS  Article  Google Scholar 

  31. 31

    Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352: 1685–1695

    CAS  Article  Google Scholar 

  32. 32

    Grosser N et al. (2004) Rosuvastatin upregulates the antioxidant defense protein heme oxygenase-1. Biochem Biophys Res Commun 325: 871–876

    CAS  Article  Google Scholar 

  33. 33

    Lee T-S et al. (2004) Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation 110: 1296–1302

    CAS  Article  Google Scholar 

  34. 34

    Madonna R et al. (2005) Simvastatin attenuates expression of cytokine-inducible nitric-oxide synthase in embryonic cardiac myoblasts. J Biol Chem 280: 13503–13511

    CAS  Article  Google Scholar 

  35. 35

    O'Shaughnessy JA et al. (2002) Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin Cancer Res 8: 314–346

    Google Scholar 

  36. 36

    Sporn MB (1991) Carcinogenesis and cancer: different perspectives on the same disease. Cancer Res 51: 6215–6218

    CAS  Google Scholar 

  37. 37

    Sledge GW Jr (2003) Gemcitabine combined with paclitaxel or paclitaxel/trastuzumab in metastatic breast cancer. Semin Oncol 30: 19–21

    CAS  Article  Google Scholar 

  38. 38

    Giaccone G (2005) Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer. J Clin Oncol 23: 3235–3242

    CAS  Article  Google Scholar 

  39. 39

    Lu C et al. (2003) Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors. J Natl Cancer Inst 95: 1825–1833

    CAS  Article  Google Scholar 

  40. 40

    Luo J et al. (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4: 257–262

    CAS  Article  Google Scholar 

  41. 41

    Sansal I and Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 14: 2954–2963

    Article  Google Scholar 

  42. 42

    Tsao AS et al. (2003) Increased phospho-Akt (SER483) expression in bronchial dysplasia: implications for lung cancer prevention studies. Cancer Epidemiol Biomarkers Prev 12: 660–664

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Balsara BR et al. (2004) Frequent activation of Akt in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 25: 2053–2059

    CAS  Article  Google Scholar 

  44. 44

    Thompson JE and Thompson CB (2004) Putting the Rap on Akt. J Clin Oncol 22: 4217–4226

    CAS  Article  Google Scholar 

  45. 45

    Sekulic A et al. (2002) A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res 60: 3504–3513

    Google Scholar 

  46. 46

    Darnell JE Jr (2002) Transcription factors as targets for cancer therapy. Nat Rev Cancer 2: 740–749

    CAS  Article  Google Scholar 

  47. 47

    Pikarsky E et al. (2004) NF-κB functions as a tumor promoter in inflammation-associated cancer. Nature 431: 461–466

    CAS  Article  Google Scholar 

  48. 48

    Greten FR et al. (2004) IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118: 285–296

    CAS  Article  Google Scholar 

  49. 49

    Darnell JE Jr (2005) Validating Stat3 in cancer therapy. Nat Med 11: 595–596

    CAS  Article  Google Scholar 

  50. 50

    Clevenger CV (2004) Roles and regulation of Stat family transcription factors in human breast cancer. Am J Pathol 165: 1449–1460

    CAS  Article  Google Scholar 

  51. 51

    Yu H and Jove R (2004) The Stats of cancer—new molecular targets come of age. Nat Rev Cancer 4: 97–105

    CAS  Article  Google Scholar 

  52. 52

    O'Shea JJ et al. (2004) A new modality for immunosuppression: targeting the JAK/Stat pathway. Nat Rev Drug Disc 3: 555–564

    CAS  Article  Google Scholar 

  53. 53

    Petty WJ et al. (2003) Cyclin D1 as a target for chemoprevention. Lung Cancer 41 (Suppl): S155–S161

    Article  Google Scholar 

  54. 54

    Ma Y et al. (2005) Retinoid targeting of different D-type cyclins through distinct chemopreventive mechanisms. Cancer Res 65: 6476–6483

    CAS  Article  Google Scholar 

  55. 55

    Leaf C (2004) Why we're losing the war on cancer (and how to win it). Fortune 149: 77–96

    Google Scholar 

  56. 56

    Rendi MH et al. (2004) The selective estrogen receptor modulator arzoxifene and the rexinoid LG100268 cooperate to promote transforming growth factor beta-dependent apoptosis in breast cancer. Cancer Res 64: 3566–3571

    CAS  Article  Google Scholar 

  57. 57

    Sporn MB (1996) The war on cancer. Lancet 347: 1377–1381

    CAS  Article  Google Scholar 

  58. 58

    Nathan C (2002) Points of control in inflammation. Nature 420: 846–852

    CAS  Article  Google Scholar 

  59. 59

    Marnett LG et al. (2003) Endogenous generation of reactive oxidants and electrophiles and their reactions with DNA and protein. J Clin Invest 111: 583–593

    CAS  Article  Google Scholar 

  60. 60

    Libby P (2002) Inflammation in atherosclerosis. Nature 420: 868–874

    CAS  Article  Google Scholar 

  61. 61

    Beal MF (2003) Mitochondria, oxidative damage, and inflammation in Parkinson's disease. Ann N Y Acad Sci 991: 120–131

    CAS  Article  Google Scholar 

  62. 62

    McGeer EG and McGeer PL (2003) Inflammatory processes in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 27: 741–749

    CAS  Article  Google Scholar 

  63. 63

    Nguyen T et al. (2005) Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem [10.1074/jbc.M503074200]

  64. 64

    Eggler AL et al. (2005) Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc Natl Acad Sci USA 102: 10070–10075

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank Carl Nathan, Paul Talalay, Thomas Kensler, Anita Roberts, and Clifton Leaf for valuable discussions. Megan Padgett has provided expert assistance in the preparation of this review. Supported by grants from the National Cancer Institute (CA-78814), the National Foundation for Cancer Research, and members of the Dartmouth College Class of 1934.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Michael B Sporn.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sporn, M., Liby, K. Cancer chemoprevention: scientific promise, clinical uncertainty. Nat Rev Clin Oncol 2, 518–525 (2005). https://doi.org/10.1038/ncponc0319

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing