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.

  • Review Article
  • Published:

Chemoprevention strategies for pancreatic cancer

Nature Reviews Gastroenterology & Hepatology volume 7, pages 347–356 (2010)Cite this article

Subjects

Abstract

Pancreatic cancer has a poor prognosis and is often diagnosed at an advanced stage, which makes it difficult to treat. The low survival rate of patients with pancreatic cancer points towards an increased need for novel therapeutic and chemopreventive strategies and also early detection of this disease. Increased consumption of fruits and vegetables has been associated with a reduced risk of pancreatic cancer. Synthetic and natural, diet-derived bioactive compounds have been evaluated as pancreatic cancer chemopreventive agents and have demonstrated various degrees of efficacy in cellular and in vivo animal models. Some chemopreventive agents (for example, curcumin or resveratrol) have also been reported to sensitize pancreatic cancer cells to standard chemotherapeutic drugs (for example, gemcitabine or erlotinib), which suggests that chemopreventive agents could potentially be used as potentiators of standard chemotherapy. Few clinical trials of pancreatic cancer chemopreventive agents have been completed and some are in early phases. Further development of pancreatic cancer chemopreventive agents may prove to be tremendously valuable for individuals at high risk of developing pancreatic cancer and patients who present with premalignant lesions. This Review discusses the current state of the pancreatic cancer chemoprevention field and highlights the challenges ahead.

Key Points

  • Pancreatic cancer has a low survival rate, which has not improved in the past few decades; current chemotherapeutic treatment is not effective

  • A great deal of research interest has been directed towards evaluating natural and synthetic chemopreventive agents in cellular and animal models of pancreatic cancer

  • Few pancreatic cancer clinical trials with chemopreventive agents have been completed; more trials are in early phases

  • Pancreatic cancer chemopreventive agents could be useful for individuals who are at high risk of developing cancer or who present with premalignant lesions

  • Pancreatic cancer chemopreventive agents have a potential use as potentiators of standard chemotherapy

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Examples of molecular targets in pancreatic cancer that are downregulated or upregulated by chemopreventive agents.

Similar content being viewed by others

References

  1. Jemal, A. et al. Cancer statistics, 2009. CA Cancer J. Clin. 59, 225–249 (2009).

    Article  PubMed  Google Scholar 

  2. Ghadirian, P., Lynch, H. T. & Krewski, D. Epidemiology of pancreatic cancer: an overview. Cancer Detect. Prev. 27, 87–93 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Greer, J. B., Whitcomb, D. C. & Brand, R. E. Genetic predisposition to pancreatic cancer: a brief review. Am. J. Gastroenterol. 102, 2564–2569 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. McKay, C. J., Glen, P. & McMillan, D. C. Chronic inflammation and pancreatic cancer. Best Pract. Res. Clin. Gastroenterol. 22, 65–73 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Ghaneh, P., Costello, E. & Neoptolemos, J. P. Biology and management of pancreatic cancer. Gut 56, 1134–1152 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Larsson, S. C., Hakanson, N., Permert, J. & Wolk, A. Meat, fish, poultry and egg consumption in relation to risk of pancreatic cancer: a prospective study. Int. J. Cancer 118, 2866–2870 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Nothlings, U. et al. Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. J. Natl Cancer Inst. 97, 1458–1465 (2005).

    Article  PubMed  Google Scholar 

  8. Vrieling, A. et al. Fruit and vegetable consumption and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int. J. Cancer 124, 1926–1934 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Wong, H. H. & Lemoine, N. R. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 6, 412–422 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Burris, H. A. 3rd et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Mancuso, A., Calabro, F. & Sternberg, C. N. Current therapies and advances in the treatment of pancreatic cancer. Crit. Rev. Oncol. Hematol. 58, 231–241 (2006).

    Article  PubMed  Google Scholar 

  12. Chua, Y. J. & Zalcberg, J. R. Pancreatic cancer—is the wall crumbling? Ann. Oncol. 19, 1224–1230 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Yu, X., Zhang, Y., Chen, C., Yao, Q. & Li, M. Targeted drug delivery in pancreatic cancer. Biochim. Biophys. Acta 1805, 97–104 (2010).

    CAS  PubMed  Google Scholar 

  14. Bardeesy, N. & DePinho, R. A. Pancreatic cancer biology and genetics. Nat. Rev. Cancer 2, 897–909 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. De La O, J. P. & Murtaugh, L. C. Notch and Kras in pancreatic cancer: at the crossroads of mutation, differentiation and signaling. Cell Cycle 8, 1860–1864 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Hruban, R. H. et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am. J. Pathol. 143, 545–554 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Moskaluk, C. A., Hruban, R. H. & Kern, S. E. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res. 57, 2140–2143 (1997).

    CAS  PubMed  Google Scholar 

  19. Korc, M. et al. Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J. Clin. Invest. 90, 1352–1369 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ebert, M., Yokoyama, M., Friess, H., Büchler, M. W. & Korc, M. Coexpression of the c-met proto-oncogene and hepatocyte growth factor in human pancreatic cancer. Cancer Res. 54, 5775–5778 (1994).

    CAS  PubMed  Google Scholar 

  21. Hakam, A., Fang, Q., Karl, R. & Coppola, D. Coexpression of IGF-1R and c-Src proteins in human pancreatic ductal adenocarcinoma. Dig. Dis. Sci. 48, 1972–1978 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Yamamoto, S. et al. Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin. Cancer Res. 10, 2846–2850 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Scholz, A. et al. Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 125, 891–905 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Aggarwal, B. B. et al. Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann. NY Acad. Sci. 1091, 151–169 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Hamacher, R., Schmid, R. M., Saur, D. & Schneider, G. Apoptotic pathways in pancreatic ductal adenocarcinoma. Mol. Cancer 7, 64 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Liptay, S. et al. Mitogenic and antiapoptotic role of constitutive NF-kB/Rel activity in pancreatic cancer. Int. J. Cancer 105, 735–746 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Fujioka, S. et al. Function of nuclear factor kB in pancreatic cancer metastasis. Clin. Cancer Res. 9, 346–354 (2003).

    CAS  PubMed  Google Scholar 

  28. Greer, J. B. & Whitcomb, D. C. Inflammation and pancreatic cancer: an evidence-based review. Curr. Opin. Pharmacol. 9, 411–418 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Mysliwiec, P. & Boucher, M. J. Targeting Notch signaling in pancreatic cancer patients—rationale for new therapy. Adv. Med. Sci. 54, 136–142 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. & DePinho, R. A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218–1249 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Goel, A., Kunnumakkara, A. B. & Aggarwal, B. B. Curcumin as “Curecumin”: from kitchen to clinic. Biochem. Pharmacol. 75, 787–809 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Reuter, S., Eifes, S., Dicato, M., Aggarwal, B. B. & Diederich, M. Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochem. Pharmacol. 76, 1340–1351 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Wang, W. et al. The nuclear factor-kB RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin. Cancer Res. 5, 119–127 (1999).

    CAS  PubMed  Google Scholar 

  34. Kunnumakkara, A. B. et al. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 67, 3853–3861 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Lev-Ari, S. et al. Inhibition of pancreatic and lung adenocarcinoma cell survival by curcumin is associated with increased apoptosis, down-regulation of COX-2 and EGFR and inhibition of Erk1/2 activity. Anticancer Res. 26, 4423–4430 (2006).

    CAS  PubMed  Google Scholar 

  36. Lev-Ari, S. et al. Curcumin augments gemcitabine cytotoxic effect on pancreatic adenocarcinoma cell lines. Cancer Invest. 25, 411–418 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Wang, Z., Zhang, Y., Banerjee, S., Li, Y. & Sarkar, F. H. Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer 106, 2503–2513 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Sun, M. et al. Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol. Cancer Ther. 7, 464–473 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Lev-Ari, S. et al. Curcumin synergistically potentiates the growth inhibitory and pro-apoptotic effects of celecoxib in pancreatic adenocarcinoma cells. Biomed. Pharmacother. 59 (Suppl. 2), S276–S280 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Swamy, M. V. et al. Prevention and treatment of pancreatic cancer by curcumin in combination with omega-3 fatty acids. Nutr. Cancer 60 (Suppl. 1), 81–89 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Soni, K. & Kuttan, R. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Indian J. Physiol. Pharmacol. 36, 273–275 (1992).

    CAS  PubMed  Google Scholar 

  42. Sharma, R. A. et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin. Cancer Res. 10, 6847–6854 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Cheng, A. L. et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high risk or pre-malignant lesions. Anticancer Res. 21, 2895–2900 (2001).

    CAS  PubMed  Google Scholar 

  44. Friedman, L. et al. Curcumin analogues exhibit enhanced growth suppressive activity in human pancreatic cancer cells. Anticancer Drugs 20, 444–449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Padhye, S. et al. New difluoro Knoevenagel condensates of curcumin, their Schiff bases and copper complexes as proteasome inhibitors and apoptosis inducers in cancer cells. Pharm. Res. 26, 1874–1880 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li, L., Braiteh, F. S. & Kurzrock, R. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 104, 1322–1331 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Dhillon, N. et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 14, 4491–4499 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Ding, X. Z., Henning, R. & Adrian, T. E. Lipoxygenase and cyclooxygenase metabolism: new insights in treatment and chemoprevention of pancreatic cancer. Mol. Cancer 2, 10 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tucker, O. N. et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res. 59, 987–990 (1999).

    CAS  PubMed  Google Scholar 

  50. Molina, M. A., Sitja-Arnau, M., Lemoine, M. G., Frazier, M. L. & Sinicrope, F. A. Increased cyclooxygenase-2 expression in human pancreatic carcinomas and cell lines: growth inhibition by nonsteroidal anti-inflammatory drugs. Cancer Res. 59, 4356–4362 (1999).

    CAS  PubMed  Google Scholar 

  51. Kokawa, A. et al. Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors. Cancer 91, 333–338 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Wenger, F. A. et al. Effects of Celebrex and Zyflo on BOP-induced pancreatic cancer in Syrian hamsters. Pancreatology 2, 54–60 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Xu, X. F. et al. Selective inhibition of cyclooxygenase-2 suppresses the growth of pancreatic cancer cells in vitro and in vivo. Tohoku J. Exp. Med. 215, 149–157 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Wei, D. et al. Celecoxib inhibits vascular endothelial growth factor expression and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res. 64, 2030–2038 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Mukherjee, P. et al. Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition. J. Immunol. 182, 216–224 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Dragovich, T. et al. Gemcitabine plus celecoxib in patients with advanced or metastatic pancreatic adenocarcinoma: results of a phase II trial. Am. J. Clin. Oncol. 31, 157–162 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Phase III Trial of Gemcitabine, Curcumin and Celebrex in Patients with Advance or Inoperable Pancreatic Cancer. ClinicalTrials.gov [online], (2010).

  58. Funahashi, H. et al. Delayed progression of pancreatic intraepithelial neoplasia in a conditional KrasG12D mouse model by a selective cyclooxygenase-2 inhibitor. Cancer Res. 67, 7068–7071 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Ding, X. Z., Tong, W. G. & Adrian, T. E. Blockade of cyclooxygenase-2 inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Anticancer Res. 20, 2625–2631 (2000).

    CAS  PubMed  Google Scholar 

  60. Takahashi, M. et al. Effects of various prostaglandin synthesis inhibitors on pancreatic carcinogenesis in hamsters after initiation with N-nitrosobis(2-oxopropyl)amine. Carcinogenesis 11, 393–395 (1990).

    Article  CAS  PubMed  Google Scholar 

  61. Anderson, K. E, Johnson, T. W., Lazovich, D. & Folsom, A. R. Association between nonsteroidal anti-inflammatory drug use and the incidence of pancreatic cancer. J. Natl Cancer Inst. 94, 1168–1171 (2002).

    Article  PubMed  Google Scholar 

  62. Schernhammer, E. S. et al. A prospective study of aspirin use and the risk of pancreatic cancer in women. J. Natl Cancer Inst. 96, 22–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Takada, M. et al. Suppression of human pancreatic carcinoma cell growth and invasion by epigallocatechin-3-gallate. Pancreas 25, 45–48 (2002).

    Article  PubMed  Google Scholar 

  64. Lyn-Cook, B. D. et al. Chemopreventive effects of tea extracts and various components on human pancreatic and prostate tumor cells in vitro. Nutr. Cancer 35, 80–86 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Takabayashi, F., Harada, N., Tahara, S., Kaneko, T. & Hara, Y. Effect of green tea catechins on the amount of 8-hydroxydeoxyguanosine (8-OHdG) in pancreatic and hepatic DNA after a single administration of N-nitrosobis(2-oxopropyl)amine (BOP). Pancreas 15, 109–112 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Majima, T., Tsutsumi, M., Nishino, H., Tsunoda, T. & Konishi, Y. Inhibitory effects of beta-carotene, palm carotene, and green tea polyphenols on pancreatic carcinogenesis initiated by N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters. Pancreas 16, 13–18 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Shibata, A., Mack, T. M., Paganini-Hill, A., Ross, R. K. & Henderson, B. E. A prospective study of pancreatic cancer in the elderly. Int. J. Cancer 58, 46–49 (1994).

    Article  CAS  PubMed  Google Scholar 

  68. Whittemore, A. S., Paffenbarger, R. S. Jr, Anderson, K. & Halpern, J. Early precursors of pancreatic cancer in college men. J. Chronic Dis. 36, 251–256 (1983).

    Article  CAS  PubMed  Google Scholar 

  69. Zatonski, W. A. et al. Cigarette smoking, alcohol, tea and coffee consumption and pancreas cancer risk: a case-control study from Opole, Poland. Int. J. Cancer 53, 601–607 (1993).

    Article  CAS  PubMed  Google Scholar 

  70. Ji, B. T. et al. Green tea consumption and the risk of pancreatic and colorectal cancers. Int. J. Cancer 70, 255–258 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. Lin, Y. et al. Green tea consumption and the risk of pancreatic cancer in Japanese adults. Pancreas 37, 25–30 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Luo, J. et al. Green tea and coffee intake and risk of pancreatic cancer in a large-scale, population-based cohort study in Japan (JPHC study). Eur. J. Cancer Prev. 16, 542–548 (2007).

    Article  PubMed  Google Scholar 

  73. Harnack, L. J. et al. Smoking, alcohol, coffee, and tea intake and incidence of cancer of the exocrine pancreas: the Iowa Women's Health Study. Cancer Epidemiol. Biomarkers Prev. 6, 1081–1086 (1997).

    CAS  PubMed  Google Scholar 

  74. Mack, T. M., Yu, M. C., Hanisch, R. & Henderson, B. E. Pancreas cancer and smoking, beverage consumption, and past medical history. J. Natl Cancer Inst. 76, 49–60 (1986).

    CAS  PubMed  Google Scholar 

  75. Heilbrun, L. K., Nomura, A. & Stemmermann, G. N. Black tea consumption and cancer risk: a prospective study. Br. J. Cancer 54, 677–683 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mizuno, S. et al. A multi-institute case–control study on the risk factors of developing pancreatic cancer. Jpn J. Clin. Oncol. 22, 286–291 (1992).

    CAS  PubMed  Google Scholar 

  77. Chow, H.-H. S. et al. Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol. Biomarkers Prev. 10, 53–58 (2001).

    CAS  PubMed  Google Scholar 

  78. Chow, H. H. et al. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin. Cancer Res. 9, 3312–3319 (2003).

    CAS  PubMed  Google Scholar 

  79. Appel, M. J., Roverts, G. & Woutersen, R. A. Inhibitory effects of micronutrients on pancreatic carcinogenesis in azaserine-treated rats. Carcinogenesis 12, 2157–2161 (1991).

    Article  CAS  PubMed  Google Scholar 

  80. Rautalahti, M. T. et al. The effects of supplementation with α-tocopherol and β-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer 86, 37–42 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Raut, C. P., McConkey, D. J. & Abbruzzese, J. L. in Cancer Chemoprevention, volume 2: Strategies for Cancer Chemoprevention (eds Kelloff, G. I., Hawk, E. T. & Sigman, C. C.) 489–499 (Humana Press Inc., Totowa, 2005).

    Book  Google Scholar 

  82. Chiang, K. C. & Chen, T. C. Vitamin D for the prevention and treatment of pancreatic cancer. World J. Gastroenterol. 15, 3349–3354 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kawa, S. et al. Vitamin D analogues up-regulate p21 and p27 during growth inhibition of pancreatic cancer cell lines. Br. J. Cancer 76, 884–889 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Colston, K. W., James, S. Y., Ofori-Kuragu, E. A., Binderup, L. & Grant, A. G. Vitamin D receptors and anti-proliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro. Br. J. Cancer 76, 1017–1020 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Skinner, H. G. et al. Vitamin D intake and the risk for pancreatic cancer in two cohort studies. Cancer Epidemiol. Biomarkers Prev. 15, 1688–1695 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Stolzenberg-Solomon, R. Z. et al. A prospective nested case–control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res. 66, 10213–10219 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Stolzenberg-Solomon, R. Z. et al. Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial. Cancer Res. 69, 1439–1447 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Evans, T. R. et al. A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer. Br. J. Cancer 86, 680–685 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Heisler, T., Towfigh, S., Simon, N., Liu, C. & McFadden, D. W. Peptide YY augments gross inhibition by vitamin E succinate of human pancreatic cancer cell growth. J. Surg. Res. 88, 23–25 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Ohlsson, B., Albrechtsson, E. & Axelson, J. Vitamins A and D but not E and K decreased the cell number in human pancreatic cancer cell lines. Scand. J. Gastroenterol. 39, 882–885 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Kelloff, G. J. et al. Clinical development plan: vitamin E. J. Cell. Biochem. Suppl. 20, 282–299 (1994).

    CAS  PubMed  Google Scholar 

  92. Stolzenberg-Solomon, R. Z. et al. Vitamin E intake, α-tocopherol status, and pancreatic cancer in a cohort of male smokers. Am. J. Clin. Nutr. 89, 584–591 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Kelloff, G. J. et al. Farnesyl protein transferase inhibitors as potential cancer chemopreventives. Cancer Epidemiol. Biomarkers Prev. 6, 267–282 (1997).

    CAS  PubMed  Google Scholar 

  94. Stark, M. J., Burke, Y. D., McKinzie, J. H., Ayoubi, A. S. & Crowell, P. L. Chemotherapy of pancreatic cancer with the monoterpene perillyl alcohol. Cancer Lett. 96, 15–21 (1995).

    Article  CAS  PubMed  Google Scholar 

  95. Stayrook, K. R., McKinzie, J. H., Burke, Y. D., Burke, Y. A. & Crowell, P. L. Induction of the apoptosis-promoting protein Bak by perillyl alcohol in pancreatic ductal adenocarcinoma relative to untransformed ductal epithelial cells. Carcinogenesis 18, 1655–1658 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Burke, Y. D., Stark, M. J., Roach, S. L., Sen, S. E. & Crowell, P. L. Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol. Lipids 32, 151–156 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Wiseman, D. A., Werner, S. R. & Crowell, P. L. Cell cycle arrest by the isoprenoids perillyl alcohol, geraniol, and farnesol is mediated by p21Cip1 and p27Kip1 in human pancreatic adenocarcinoma cells. J. Pharmacol. Exp. Ther. 320, 1163–1170 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Matos, J. M. et al. A pilot study of perillyl alcohol in pancreatic cancer. J. Surg. Res. 147, 194–199 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Fahey, J. W., Zalcmann, A. T. & Talalay, P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 56, 5–51 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Kallifatidis, G. et al. Sulforaphane targets pancreatic tumor-initiating cells by NF-kappaB-induced antiapoptotic signaling. Gut 58, 949–963 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Srivastava, S. K. & Singh, S. V. Cell cycle arrest, apoptosis induction and inhibition of nuclear factor kappa B activation in anti-proliferative activity of benzyl isothiocyanate against human pancreatic cancer cells. Carcinogenesis 25, 1701–1709 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Sahu, R. P., Zhang, R., Batra, S., Shi, Y. & Srivastava, S. K. Benzyl isothiocyanate-mediated generation of reactive oxygen species causes cell cycle arrest and induces apoptosis via activation of MAPK in human pancreatic cancer cells. Carcinogenesis 30, 1744–1753 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Basu, A. & Haldar, S. Anti-proliferative and proapoptotic effects of benzyl isothiocyanate on human pancreatic cancer cells is linked to death receptor activation and RasGAP/Rac1 down-modulation. Int. J. Oncol. 35, 593–599 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Son, H. Y. et al. Modifying effects of 4-phenylbuthyl isothiocyanate on N-nitrosobis(2-oxopropyl)amine-induced tumorigenesis in hamsters. Cancer Lett. 160, 141–147 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Nishikawa, A. et al. Chemopreventive effects of phenethyl isothiocyanate on lung and pancreatic tumorigenesis in N-nitrosobis(2-oxopropyl)amine-treated hamsters. Carcinogenesis 17, 1381–1384 (1996).

    Article  CAS  PubMed  Google Scholar 

  106. Li, Y. et al. Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line. Pancreas 28, e90–e95 (2004).

    Article  PubMed  Google Scholar 

  107. Wang, Z., Zhang, Y., Banerjee, S., Li, Y. & Sarker, F. H. Inhibition of nuclear factor kB activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells. Int. J. Cancer 118, 1930–1936 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. El-Rayes, B. E. et al. Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kB. Cancer Res. 66, 10553–10559 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Ding, X. Z. & Adrian, T. E. Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Pancreas 25, e71–e76 (2002).

    Article  PubMed  Google Scholar 

  110. Harikumar, K. B. et al. Resveratrol, a multitarget agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer. Int. J. Cancer doi:10.1002/ijc.25041.

  111. Zhang, R., Humphreys, I., Sahu, R. P., Shi, Y. & Srivastava, S. K. In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. Apoptosis 13, 1465–1478 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Azmi, A. S. et al. Chemoprevention of pancreatic cancer: characterization of Par-4 and its modulation by 3,3′ diindolylmethane (DIM). Pharm. Res. 25, 2117–2124 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ali, S. et al. Apoptosis-inducing effect of erlotinib is potentiated by 3,3′-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer. Mol. Cancer Ther. 7, 1708–1719 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Schneider, M. B. et al. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 120, 1263–1270 (2001).

    Article  CAS  PubMed  Google Scholar 

  115. Kisfalvi, K., Eibl, G., Sinnett-Smith, J. & Rozengurt, E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 69, 6539–6545 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Li, D., Yeung, S. C., Hassan, M. M., Konopleva, M. & Abbruzzese, J. L. Anti-diabetic therapies affect risk of pancreatic cancer. Gastroenterology 137, 482–488 (2009).

    Article  PubMed  Google Scholar 

  117. Ulrich, C. D. Pancreatic cancer in hereditary pancreatitis: consensus guidelines for prevention, screening and treatment. Pancreatology 1, 416–422 (2001).

    Article  CAS  PubMed  Google Scholar 

  118. Brand, R. E. et al. Advances in counseling and surveillance of patients at risk for pancreatic cancer. Gut 56, 1460–1469 (2006).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported in part by funds from Shirley Hobbs Martin Memorial Fund (awarded to R. E. Brand) and the National Cancer Institute grant R01CA101753 (awarded to S. V. Singh). We thank D. C. Whitcomb for helpful suggestions and feedback on the manuscript. We apologize to the investigators whose work could not be cited due to space limitations.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, Hepatology and Nutrition, University of Pittsburgh School of Medicine, 5117 Centre Avenue, 2.31 Hillman Cancer Center, Pittsburgh, 15213, PA, USA

    Silvia D. Stan & Randall E. Brand

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 5117 Centre Avenue, 2.31 Hillman Cancer Center, Pittsburgh, 15213, PA, USA

    Shivendra V. Singh

Authors
  1. Silvia D. Stan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shivendra V. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Randall E. Brand
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Silvia D. Stan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stan, S., Singh, S. & Brand, R. Chemoprevention strategies for pancreatic cancer. Nat Rev Gastroenterol Hepatol 7, 347–356 (2010). https://doi.org/10.1038/nrgastro.2010.61

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2010.61

This article is cited by

Search

Advanced 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