Pharmaceutical Research

, Volume 27, Issue 6, pp 1138–1145 | Cite as

Multiple Berry Types Prevent N-nitrosomethylbenzylamine-Induced Esophageal Cancer in Rats

  • Gary D. Stoner
  • Li-Shu Wang
  • Claire Seguin
  • Claudio Rocha
  • Kristen Stoner
  • Steven Chiu
  • A. Douglas Kinghorn
Research Paper

ABSTRACT

Purpose

The present study compared the ability of different berry types to prevent chemically-induced tumorigenesis in the rat esophagus. We also determined if berries influence the levels of inflammatory cytokines in the serum of carcinogen-treated rats.

Methods

Rats were treated with the carcinogen N-nitrosomethylbenzylamine (NMBA) for 5 weeks, then placed on diets containing 5% of either black or red raspberries, strawberries, blueberries, noni, açaí or wolfberry until the end of the study. The effects of the berries on tumor incidence, multiplicity and size were determined, as well as their effects on the levels of selected inflammatory cytokines in serum.

Results

All berry types were about equally effective in inhibiting NMBA-induced tumorigenesis in the rat esophagus. They also reduced the levels of the serum cytokines, interleukin 5 (IL-5) and GRO/KC, the rat homologue for human interleukin-8 (IL-8), and this was associated with increased serum antioxidant capacity.

Conclusions

Seven berry types were about equally capable of inhibiting tumor progression in the rat esophagus in spite of known differences in levels of anthocyanins and ellagitannins. Serum levels of IL-5 and GRO/KC (IL-8) may be predictive of the inhibitory effect of chemopreventive agents on rat esophageal carcinogenesis.

KEY WORDS

berries chemoprevention esophagus rat 

ABBREVIATIONS

AP-1

Activator protein-1

AIN-76A

American Institute of Nutrition-76A

BRBs

black raspberries

BBs

blueberries

DMSO

dimethylsulfoxide

EGF

epidermal growth factor

IL-8

GRO/KC

IFNγ

interferon-gamma

IL

interleukin

NMBA

N-nitrosomethylbenzylamine

RRBs

red raspberries

STRWs

strawberries

TPA

12-O-tetradecanolyphorbol-13-acetate

TNF-α

tumor necrosis factor-alpha

REFERENCES

  1. 1.
    Seeram NP. Berry fruits: Compositional elements, biochemical activities, and the impact of their intake on human health, performance, and disease. J Agric Food Chem. 2008;56:627–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Seeram NP. Recent trends and advances in berry health benefits research. J Agric Food Chem; 2009.Google Scholar
  3. 3.
    Cerda B, Tomas-Barberan FA, Espin JC. Metabolism of antioxidant and chemopreventive ellagitannins from strawberries, raspberries, walnuts, and oak-aged wine in humans: identification of biomarkers and individual variability. J Agric Food Chem. 2004;53:227–35.CrossRefGoogle Scholar
  4. 4.
    Wang L-S, Hecht SS, Carmella SG, Yu N, Larue B, Henry C et al. Anthocyanins in black raspberries prevent esophageal tumors in rats. Cancer Prev Res. 2009;2:84–93.CrossRefGoogle Scholar
  5. 5.
    Stoner GD, Wang L-S, Casto BC. Laboratory and clinical studies of cancer chemoprevention by antioxidants in berries. Carcinogenesis. 2008;29:1665–74.CrossRefPubMedGoogle Scholar
  6. 6.
    Kresty LA, Morse MA, Morgan C, Carlton PS, Lu J, Gupta A et al. Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries. Cancer Res. 2001;61:6112–9.PubMedGoogle Scholar
  7. 7.
    Harris GK, Gupta A, Nines RG, Kresty LA, Habib SG, Frankel WL et al. Effects of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2′-deoxyguanosine levels in the Fischer 344 rat. Nutr Cancer. 2001;40:125–33.CrossRefPubMedGoogle Scholar
  8. 8.
    Casto BC, Kresty LA, Kraly CL, Pearl DK, Knobloch TJ, Schut HA et al. Chemoprevention of oral cancer by black raspberries. Anticancer Res. 2002;22:4005–15.PubMedGoogle Scholar
  9. 9.
    Aiyer HS, Srinivasan C, Gupta RC. Dietary berries and ellagic acid diminish estrogen-mediated mammary tumorigenesis in ACI rats. Nutr Cancer. 2008;60:227–34.CrossRefPubMedGoogle Scholar
  10. 10.
    Duncan FJ, Martin JR, Wulff BC, Stoner GD, Tober KL, Oberyszyn TM et al. Topical treatment with black raspberry extract reduces cutaneous UVB-induced carcinogenesis and inflammation. Cancer Prev Res. 2009;2:665–72.CrossRefGoogle Scholar
  11. 11.
    Stoner GD, Wang L-S, Zikri N, Chen T, Hecht SS, Huang C et al. Cancer prevention with freeze-dried berries and berry components. Sem Cancer Biol. 2007;17:403–10.CrossRefGoogle Scholar
  12. 12.
    Stoner GD, Dombkowski AA, Reen RK, Cukovic D, Salagrama S, Wang L-S et al. Carcinogen-altered genes in rat esophagus positively modulated to normal levels of expression by both black raspberries and phenethyl isothiocyanate. Cancer Res. 2008;68:6460–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Carlton PS, Kresty LA, Siglin JC, Morse MA, Lu J, Morgan C et al. Inhibition of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus by dietary freeze-dried strawberries. Carcinogenesis. 2001;22:441–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Stoner GD, Chen T, Kresty LA, Aziz R, Reinemann MT, Nines R. Protection against esophageal cancer in rodents with lyophilized berries: potential mechanisms. Nutr Cancer. 2006;54:33–46.CrossRefPubMedGoogle Scholar
  15. 15.
    Wang L-S, Stoner GD. Anthocyanins and their role in cancer prevention. Cancer Lett. 2008;269:281–90.CrossRefPubMedGoogle Scholar
  16. 16.
    Su B-N, Pawlus AD, Jung HD, Keller WJ, McLaughlin J-L, Kinghorn AD. Chemical constitutents of the fruits of Morinda citrifolia (Noni) and their antioxidant activity. J Nat Prod. 2005;68:592–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Pawlus AD, Su B-N, Keller WJ, Kinghorn AD. An anthraquinone with potent quinine reductase –inducing activity and other constituents of the fruits of Morinda citrifolia. J Nat Prod. 2005;68:1720–2.CrossRefPubMedGoogle Scholar
  18. 18.
    Liu G, Bode A, Ma W-Y, Sang S, Ho C-T, Dong Z. Two novel glycosides from the fruits of Morinda Citrifolia (Noni) inhibit AP-1 transactivation and cell transformation in the mouse epidermal JB6 cell line. Cancer Res. 2001;61:5749–56.PubMedGoogle Scholar
  19. 19.
    Chin Y-W, Chai H-B, Keller WJ, Kinghorn AD. Lignans and other constituents of the fruits of Euterpe oleracea (Acai) with antioxidant and cytoprotective activities. J Agric Food Chem. 2008;56:7759–64.CrossRefPubMedGoogle Scholar
  20. 20.
    Del Pozo-Insfran D, Percival SS, Talcott ST. Acai (Euterpe oleracea Mart.) Polyphenolics in their glycoside and aglycone forms induce apoptosis of HL-60 leukemia cells. J Agric Food Chem. 2006;54:1222–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Gan L, Hua Zhang S, Liang Yang X, Bi Xu H. Immunomodulation and antitumor activity by a polysaccharide-protein complex from Lycium barbarum. Int Immunopharmacol. 2004;4:563–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Stoner GD, Gupta A. Etiology and chemoprevention of esophageal squamous cell carcinoma. Carcinogenesis. 2001;22:1737–46.CrossRefPubMedGoogle Scholar
  23. 23.
    Mandal S, Stoner GD. Inhibition of N-nitrosobenzylmethylamine induced esophageal tumorigenesis in rats by ellagic acid. Carcinogenesis. 1990;11:55–61.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang SY, Lin H-S. Antioxidant activity in fruits and leaves of blackberry, raspberry, and strawberry varies with cultivar and developmental stage. J Agric Food Chem. 2000;48:140–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Wada L, Ou B. Antioxidant activity and phenolic content of Oregon caneberries. J Agric Food Chem. 2002;50:3495–500.CrossRefPubMedGoogle Scholar
  26. 26.
    Ehlenfeldt MK, Prior RL. Oxygen radical absorbance capacity (ORAC) and phenolic and anthocyanin concentrations in fruit and leaf tissues of highbush blueberry. J Agric Food Chem. 2001;49:2222–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Moyer RA, Hummer KE, Finn CE, Frei B, Wrolstad RE. Anthocyanins, phenolics, and antioxidant capacity in diverse small fruits: vaccinium, rubus, and ribes. J Agric Food Chem. 2002;50:519–25.CrossRefPubMedGoogle Scholar
  28. 28.
    Wang SY, Chen C-T, Sciarappa W, Wang CY, Camp MJ. Fruit quality, antioxidant capacity, and flavonoid content of organically and conventionally grown blueberries. J Agric Food Chem. 2008;56:5788–94.CrossRefPubMedGoogle Scholar
  29. 29.
    Asami DK, Hong Y-J, Barrett DM, Mitchell AE. Comparison of the total phenolic and ascorbic acid content of freeze-dried and air-dried marionberry, strawberry, and corn grown using conventional, organic, and sustainable agricultural practices. J Agric Food Chem. 2003;51:1237–41.CrossRefPubMedGoogle Scholar
  30. 30.
    Chen-Blanco Y, Vaillant F, Perez AM, Reynes M, Brillouet J-M, Brat P. The noni fruit (Morinda citrifolia L.): a review of agricultural research, nutritional and therapeutic properties. J Food Comp Anal. 2006;19:645–54.CrossRefGoogle Scholar
  31. 31.
    Gross PM, Zhang X, Zhang R. Wolfberry: nature’s bounty of nutrition and health, BookSurge Publishing, http://www.wolfberry.org, 2006.
  32. 32.
    Schauss AG, Wu X, Prior RL, Ou B, Patel D, Huang D et al. Phytochemical and nutrient composition of the freeze-dried Amazonian palm berry, Euterpe oleraceae Mart. (Acai). J Agric Food Chem. 2006;54:8598–603.CrossRefPubMedGoogle Scholar
  33. 33.
    Pacheco-Palencia LA, Mertens-Talcott S, Talcott ST. Chemical composition, antioxidant properties, and thermal stability of a phytochemical enriched oil from Acai (Euterpe oleracea Mart.). J Agric Food Chem. 2008;56:4631–6.CrossRefPubMedGoogle Scholar
  34. 34.
    He J, Magnuson BA, Guisti MM. Analysis of anthocyanins in rat intestinal contents-impact of anthocyanin chemical structure on fecal excretion. J Agric Food Chem. 2005;53:2859–66.CrossRefPubMedGoogle Scholar
  35. 35.
    Stoner GD, Sardo C, Apseloff G, Mullet D, Wargo W, Pound V et al. Pharmacokinetics of anthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 days. J Clin Pharmacol. 2005;45:1153–64.CrossRefPubMedGoogle Scholar
  36. 36.
    Stoner GD. Foodstuffs for preventing cancer: the preclinical and clinical development of berries. Cancer Prev Res. 2009;2:187–94.CrossRefGoogle Scholar
  37. 37.
    Cheng CY, Chung WY, Szeto YT, Benzie IFF. Fasting plasma zeaxanthin response to Fructus barbarum L. (wolfberry; Kei Tze) in a food-based human supplementation trial. Br J Nutr. 2005;93:123–30.CrossRefPubMedGoogle Scholar
  38. 38.
    Tian M, Wang M. Studies on extraction, isolation and composition of Lycium barbarum polysaccharides. Zhongguo Zhong Yao Za Zhi. 2006;31:1063–7.Google Scholar
  39. 39.
    Taşkin EI, Akgün-Dar K, Kapucu A, Osanç E, Doğruman H, Eraltan H et al. Apoptosis-inducing effects of Morinda citrifolia L. and doxorubicin on the Ehrlich ascites tumor in Balb-c mice. Cell Biochem Funct. 2009;27:542–6.CrossRefPubMedGoogle Scholar
  40. 40.
    Lichtenthäler R, Rodrigues R, Maia J, Papagiannopoulos M, Fabricius H, Marx F. Total oxidant scavenging capacities of Euterpe oleracea Mart. (Acaí) fruits. Int J Food Sci Nutr. 2005;56:53–64.CrossRefPubMedGoogle Scholar
  41. 41.
    Tsujiuchi T, Sasaki Y, Tsutsumi M, Konishi Y. Elevated expression of interleukins in lung adenocarcinomas induced by N-Nitrosobis(2-hydroxypropyl)amine in rats. Jpn J Cancer Res. 2000;91:955–9.PubMedGoogle Scholar
  42. 42.
    Koch A, Polverini P, Kunkel S, Harlow L, DiPietro L, Elner V et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science. 1992;258:1798–801.CrossRefPubMedGoogle Scholar
  43. 43.
    Chen G, Chu Y, Chak E, Leung B, Poon W. Induction of apoptosis in glioma cells by molecules released from activated macrophages. J Neurooncol. 2002;57:179–86.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Gary D. Stoner
    • 1
    • 3
  • Li-Shu Wang
    • 1
  • Claire Seguin
    • 1
  • Claudio Rocha
    • 1
  • Kristen Stoner
    • 1
  • Steven Chiu
    • 1
  • A. Douglas Kinghorn
    • 2
  1. 1.Department of Internal Medicine and Comprehensive Cancer Center, College of MedicineThe Ohio State UniversityColumbusUSA
  2. 2.Division of Medicinal Chemistry and Pharmacognosy, College of PharmacyThe Ohio State UniversityColumbusUSA
  3. 3.Department of Internal MedicineOhio State University Comprehensive Cancer CenterColumbusUSA

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