Natural Products as Anti-inflammatory Agents

  • Gary StonerEmail author
  • Li-Shu Wang
Part of the Energy Balance and Cancer book series (EBAC, volume 7)


Inflammation is triggered by numerous factors including oxidative stress, environmental pollutants, microbial agents, and physical damage to tissues. Chronic inflammation, characterized by a prevalence of macrophages and lymphocytes in the affected tissues and the overexpression of a host of cellular cytokines, chemokines, and inflammatory enzymes, promotes all stages of cancer development including initiation, promotion, cell transformation, angiogenesis, invasion, and metastasis. This chapter describes some key mechanisms by which naturally occurring dietary compounds, either alone or in combination, reduce the harmful effects of inflammation and the risk for cancer development. The most extensively studied compounds are a series of polyphenols which influence the inflammatory process in multiple ways including their ability to scavenge oxidative radicals, influence carcinogen activation and detoxification, and regulate expression levels of numerous transcription activators and their associated cytokines, chemokines, and inflammatory enzymes. In the past, the inhibitory effects of naturally occurring compounds, especially the polyphenols, have been attributed mainly to their intrinsic antioxidant capacity; however, it is likely that their direct binding to cellular macromolecules and the associated effects on gene transcription and translation, as well as on enzyme activity, may be equally as important.


Esophageal Squamous Cell Carcinoma Idiopathic Pulmonary Fibrosis Ellagic Acid Caffeic Acid Phenethyl Ester Tumor Necrosis Factor Production 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899PubMedGoogle Scholar
  2. 2.
    Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G (2006) Inflammation and ­cancer: how hot is the link? Biochem Pharmacol 72:1605–1621PubMedGoogle Scholar
  3. 3.
    Canavan C, Abrams KR, Mayberry J (2006) Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn’s disease. Aliment Pharmacol Ther 23:1097–1104PubMedGoogle Scholar
  4. 4.
    Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G et al (2012) Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142:46–54.e42PubMedGoogle Scholar
  5. 5.
    Clapper ML, Cooper HS, Chang W-CL (2007) Dextran sulfate sodium-induced colitis-associated neoplasia: a promising model for the development of chemopreventive interventions. Acta Pharmacol Sin 28:1450–1459PubMedGoogle Scholar
  6. 6.
    Rogers AB, Houghton J (2009) Helicobacter-based mouse models of digestive system carcinogenesis. Methods Mol Biol 511:267–295PubMedGoogle Scholar
  7. 7.
    Satake K, Mukai R, Kato Y, Umeyama K (1986) Effects of cerulein on the normal pancreas and on experimental pancreatic carcinoma in the Syrian golden hamster. Pancreas 1:246–253PubMedGoogle Scholar
  8. 8.
    Vykhovanets EV, Resnick MI, MacLennan GT, Gupta S (2007) Experimental rodent models of prostatitis: limitations and potential. Prostate Cancer Prostatic Dis 10:15–29PubMedGoogle Scholar
  9. 9.
    McKenna IM, Waalkes MP, Chen LC, Gordon T (1997) Comparison of inflammatory lung responses in Wistar rats and C57 and DBA mice following acute exposure to cadmium oxide fumes. Toxicol Appl Pharmacol 146:196–206PubMedGoogle Scholar
  10. 10.
    Steinmetz KA, Potter JD (1991) Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control 2:427–442PubMedGoogle Scholar
  11. 11.
    Block G, Patterson B, Subar A (1992) Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 18:1–29PubMedGoogle Scholar
  12. 12.
    Willett WC (1995) Diet, nutrition, and avoidable cancer. Environ Health Perspect 103:165–170PubMedGoogle Scholar
  13. 13.
    Sun J, Chu Y-F, Wu X, Liu RH (2002) Antioxidant and antiproliferative activities of common fruits. J Agric Food Chem 50:7449–7454PubMedGoogle Scholar
  14. 14.
    Chu Y-F, Sun J, Wu X, Liu RH (2002) Antioxidant and antiproliferative activities of common vegetables. J Agric Food Chem 50:6910–6916PubMedGoogle Scholar
  15. 15.
    Kähkönen MP, Hopia AI, Heinonen M (2001) Berry phenolics and their antioxidant activity. J Agric Food Chem 49:4076–4082PubMedGoogle Scholar
  16. 16.
    Stoner GD (2004) Cancer chemoprevention: promising cancer chemoprevention agents. In: Kelloff GJ, Hawk ET, Sigman CC (eds) Chemoprevention by fruit phenolic compounds, vol 1. Humana Press, New Jersey, pp 419–435Google Scholar
  17. 17.
    Stoner GD (2003) Bioprocesses and biotechnology for functional foods and nutraceuticals. In: Neeser JR, German JB (eds) Foods and food components in the prevention of cancer; Marcel Dekker, New York, chapter 17, pp 331–373Google Scholar
  18. 18.
    Wang SY, Jiao H (2000) Scavenging capacity of berry crops on superoxide radicals, hydrogen peroxide, hydroxyl radicals, and singlet oxygen. J Agric Food Chem 48:5677–5684PubMedGoogle Scholar
  19. 19.
    Leonard SS, Cutler D, Ding M, Vallyathan V, Castranova V, Shi X (2002) Antioxidant properties of fruit and vegetable juices: more to the story than ascorbic acid. Ann Clin Lab Sci 32:193–200PubMedGoogle Scholar
  20. 20.
    Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421PubMedGoogle Scholar
  21. 21.
    Manna SK, Mukhopadhyay A, Aggarwal BB (2000) Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-κB, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 164:6509–6519PubMedGoogle Scholar
  22. 22.
    Singh S, Aggarwal BB (1995) Activation of transcription factor NF-κB is suppressed by curcumin (diferuloylmethane). J Biol Chem 270:24995–25000PubMedGoogle Scholar
  23. 23.
    Shishodia S, Majumdar S, Banerjee S, Aggarwal BB (2003) Ursolic acid inhibits nuclear factor-κB activation induced by carcinogenic agents through suppression of IκBα kinase and p65 phosphorylation. Cancer Res 63:4375–4383PubMedGoogle Scholar
  24. 24.
    Kim G-Y, Kim J-H, Ahn S-C, Lee H-J, Moon D-O, Lee C-M et al (2004) Lycopene suppresses the lipopolysaccharide-induced phenotypic and functional maturation of murine dendritic cells through inhibition of mitogen-activated protein kinases and nuclear factor-κB. Immunology 113:203–211PubMedGoogle Scholar
  25. 25.
    Shukla S, Gupta S (2004) Suppression of constitutive and tumor necrosis factor α-induced nuclear factor (NF)-κB activation and induction of apoptosis by apigenin in human prostate carcinoma PC-3 cells: correlation with down-regulation of NF-κB-responsive genes. Clin Cancer Res 10:3169–3178PubMedGoogle Scholar
  26. 26.
    Agarwal R (2000) Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. Biochem Pharmacol 60:1051–1059PubMedGoogle Scholar
  27. 27.
    Edderkaoui M, Odinokova I, Ohno I, Gukovsky I, Go VL, Pandol SJ et al (2008) Ellagic acid induces apoptosis through inhibition of nuclear factor kappa B in pancreatic cancer cells. World J Gastroenterol 14:3672–3680PubMedGoogle Scholar
  28. 28.
    Huang C, Zhang D, Li J, Tong Q, Stoner GD (2007) Differential inhibition of UV-induced activation of NF-κB and AP-1 by extracts from black raspberries, strawberries, and blueberries. Nutr Cancer 58:205–212PubMedGoogle Scholar
  29. 29.
    Orban Z, Mitsiades N, Burke TR Jr, Tsokos M, Chrousos GP (2000) Caffeic acid phenethyl ester induces leukocyte apoptosis, modulates nuclear factor-kappa B and suppresses acute inflammation. Neuroimmunomodulation 7:99–105PubMedGoogle Scholar
  30. 30.
    Yang F, Oz HS, Barve S, de Villiers WJS, McClain CJ, Varilek GW (2001) The green tea polyphenol (−)-epigallocatechin-3-gallate blocks nuclear factor-κB activation by inhibiting IκB kinase activity in the intestinal epithelial cell line IEC-6. Mol Pharmacol 60:528–533PubMedGoogle Scholar
  31. 31.
    Kim SO, Chun KS, Kundu JK, Surh YJ (2004) Inhibitory effects of [6]-gingerol on PMA-induced COX-2 expression and activation of NF-kappaB and p38 MAPK in mouse skin. Biofactors 21:27–31PubMedGoogle Scholar
  32. 32.
    Geng Z, Rong Y, Lau BHS (1997) S-Allyl cysteine inhibits activation of nuclear factor kappa B in human T cells. Free Radic Biol Med 23:345–350PubMedGoogle Scholar
  33. 33.
    Takada Y, Aggarwal BB (2004) Flavopiridol inhibits NF-κB activation induced by various carcinogens and inflammatory agents through inhibition of IκBα kinase and p65 phosphorylation. J Biol Chem 279:4750–4759PubMedGoogle Scholar
  34. 34.
    Murakami A, Song M, Ohigashi H (2007) Phenethyl isothiocyanate suppresses receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis by blocking activation of ERK1/2 and p38 MAPK in RAW264.7. Biofactors 30:1–11PubMedGoogle Scholar
  35. 35.
    Lai KC, Huang AC, Hsu SC, Kuo CL, Yang JS, Wu SH et al (2010) Benzyl isothiocyanate (BITC) inhibits migration and invasion of human colon cancer HT29 cells by inhibiting matrix metalloproteinase-2/-9 and urokinase plasminogen (uPA) through PKC and MAPK signaling pathway. J Agric Food Chem 58:2935–2942PubMedGoogle Scholar
  36. 36.
    Takada Y, Andreeff M, Aggarwal BB (2005) Indole-3-carbinol suppresses NF-κB and IκBα kinase activation, causing inhibition of expression of NF-κB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. Blood 106:641–649PubMedGoogle Scholar
  37. 37.
    Heiss E, Herhaus C, Klimo K, Bartsch H, Gerhäuser C (2001) Nuclear factor κB is a ­molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J Biol Chem 276:32008–32015PubMedGoogle Scholar
  38. 38.
    Ruiz PA, Braune A, Hölzlwimmer G, Quintanilla-Fend L, Haller D (2007) Quercetin inhibits TNF-induced NF-κB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. J Nutr 137:1208–1215PubMedGoogle Scholar
  39. 39.
    Chainy GB, Manna SK, Chaturvedi MM, Aggarwal BB (2000) Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-kappaB, AP-1, JNK, MAPKK and apoptosis. Oncogene 19:2943–2950PubMedGoogle Scholar
  40. 40.
    Suzuki YJ, Aggarwal BB, Packer L (1992) α-Lipoic acid is a potent inhibitor of NF-κB activation in human T cells. Biochem Biophys Res Commun 189:1709–1715PubMedGoogle Scholar
  41. 41.
    Valachovicova T, Slivova V, Bergman H, Shuherk J, Sliva D (2004) Soy isoflavones suppress invasiveness of breast cancer cells by the inhibition of NF-kappaB/AP-1-dependent and -independent pathways. Int J Oncol 25:1389–1395PubMedGoogle Scholar
  42. 42.
    Song Y-A, Park Y-L, Kim K-Y, Chung C-Y, Lee G-H, Cho D-H et al (2011) Black tea extract prevents lipopolysaccharide-induced NF-kappaB signaling and attenuates dextran sulfate sodium-induced experimental colitis. BMC Complement Altern Med 11:91PubMedGoogle Scholar
  43. 43.
    Wang LS, Hecht SS, Carmella SG, Yu N, Larue B, Henry C et al (2009) Anthocyanins in black raspberries prevent esophageal tumors in rats. Cancer Prev Res 2:84–93Google Scholar
  44. 44.
    Chen T, Yan F, Qian J, Guo M, Zhang H, Tang X et al (2012) Randomized phase II trial of lyophilized strawberries in patients with dysplastic precancerous lesions of the esophagus. Cancer Prev Res 5:41–50Google Scholar
  45. 45.
    Rhode J, Fogoros S, Zick S, Wahl H, Griffith K, Huang J et al (2007) Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells. BMC Complement Altern Med 7:44PubMedGoogle Scholar
  46. 46.
    Mantena SK, Katiyar SK (2006) Grape seed proanthocyanidins inhibit UV-radiation-induced oxidative stress and activation of MAPK and NF-κB signaling in human epidermal keratinocytes. Free Radic Biol Med 40:1603–1614PubMedGoogle Scholar
  47. 47.
    Sharma SD, Meeran SM, Katiyar SK (2007) Dietary grape seed proanthocyanidins inhibit UVB-induced oxidative stress and activation of mitogen-activated protein kinases and nuclear factor-kappaB signaling in in vivo SKH-1 hairless mice. Mol Cancer Ther 6:995–1005PubMedGoogle Scholar
  48. 48.
    La VD, Howell AB, Grenier D (2009) Cranberry proanthocyanidins inhibit MMP production and activity. J Dent Res 88:627–632PubMedGoogle Scholar
  49. 49.
    Feldman M, Tanabe S, Howell A, Grenier D (2012) Cranberry proanthocyanidins inhibit the adherence properties of Candida albicans and cytokine secretion by oral epithelial cells. BMC Complement Altern Med 12:6PubMedGoogle Scholar
  50. 50.
    Ravi D, Muniyappa H, Das K (2008) Caffeine inhibits UV-mediated NF-κB activation in A2058 melanoma cells: an ATM-PKCδ-p38 MAPK-dependent mechanism. Mol Cell Biochem 308:193–200PubMedGoogle Scholar
  51. 51.
    Shishodia S, Aggarwal BB (2006) Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, I kappa B kinase activation and NF-kappa B-regulated gene expression. Oncogene 25:1463–1473PubMedGoogle Scholar
  52. 52.
    Eferl R, Wagner EF (2003) AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3:859–868PubMedGoogle Scholar
  53. 53.
    Hsu T-C, Young MR, Cmarik J, Colburn NH (2000) Activator protein 1 (AP-1)- and nuclear factor κB (NF-κB)-dependent transcriptional events in carcinogenesis. Free Radic Biol Med 28:1338–1348PubMedGoogle Scholar
  54. 54.
    Zenz R, Eferl R, Scheinecker C, Redlich K, Smolen J, Schonthaler H et al (2008) Activator protein 1 (Fos/Jun) functions in inflammatory bone and skin disease. Arthritis Res Ther 10:201PubMedGoogle Scholar
  55. 55.
    Yu R, Hebbar V, Kim DW, Mandlekar S, Pezzuto JM, Kong AN (2001) Resveratrol inhibits phorbol ester and UV-induced activator protein 1 activation by interfering with mitogen-activated protein kinase pathways. Mol Pharmacol 60:217–224PubMedGoogle Scholar
  56. 56.
    Han SS, Keum YS, Seo HJ, Surh YJ (2002) Curcumin suppresses activation of NF-kappaB and AP-1 induced by phorbol ester in cultured human promyelocytic leukemia cells. J Biochem Mol Biol 35:337–342PubMedGoogle Scholar
  57. 57.
    Dong Z (2000) Effects of food factors on signal transduction pathways. Biofactors 12:17–28PubMedGoogle Scholar
  58. 58.
    Han SS, Keum Y-S, Seo H-J, Chun K-S, Lee SS, Surh Y-J (2001) Capsaicin suppresses phorbol ester-induced activation of NF-κB/Rel and AP-1 transcription factors in mouse epidermis. Cancer Lett 164:119–126PubMedGoogle Scholar
  59. 59.
    Manna SK, Sah NK, Newman RA, Cisneros A, Aggarwal BB (2000) Oleandrin suppresses activation of nuclear transcription factor-κB, activator protein-1, and c-Jun NH2-terminal kinase. Cancer Res 60:3838–3847PubMedGoogle Scholar
  60. 60.
    Lee Y-B, Ko K-C, Shi M-D, Liao Y-C, Chiang T-A, Wu P-F et al (2010) α-Mangostin, a novel dietary xanthone, suppresses TPA-mediated MMP-2 and MMP-9 expressions through the ERK signaling pathway in MCF-7 human breast adenocarcinoma cells. J Food Sci 75:H13–H23PubMedGoogle Scholar
  61. 61.
    Chen Y-C, Liang Y-C, Lin-Shiau S-Y, Ho C-T, Lin J-K (1999) Inhibition of TPA-induced protein kinase C and transcription activator protein-1 binding activities by theaflavin-3,3′-digallate from black tea in NIH3T3 cells. J Agric Food Chem 47:1416–1421PubMedGoogle Scholar
  62. 62.
    Hou D-X, Kai K, Li J-J, Lin S, Terahara N, Wakamatsu M et al (2004) Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure–activity relationship and molecular mechanisms. Carcinogenesis 25:29–36PubMedGoogle Scholar
  63. 63.
    Feng R, Lu Y, Bowman LL, Qian Y, Castranova V, Ding M (2005) Inhibition of activator protein-1, NF-κB, and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid. J Biol Chem 280:27888–27895PubMedGoogle Scholar
  64. 64.
    Feng R, Bowman LL, Lu Y, Leonard SS, Shi X, Jiang B-H et al (2004) Blackberry extracts inhibit activating protein 1 activation and cell transformation by perturbing the mitogenic signaling pathway. Nutr Cancer 50:80–89PubMedGoogle Scholar
  65. 65.
    Chen T, Hwang H, Rose ME, Nines RG, Stoner GD (2006) Chemopreventive properties of black raspberries in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis: down-regulation of cyclooxygenase-2, inducible nitric oxide synthase, and c-Jun. Cancer Res 66:2853–2859PubMedGoogle Scholar
  66. 66.
    Huang C, Li J, Song L, Zhang D, Tong Q, Ding M et al (2006) Black raspberry extracts inhibit benzo(a)pyrene diol-epoxide-induced activator protein 1 activation and VEGF ­transcription by targeting the phosphotidylinositol 3-kinase/Akt pathway. Cancer Res 66:581–587PubMedGoogle Scholar
  67. 67.
    Ding M, Lu Y, Bowman L, Huang C, Leonard S, Wang L et al (2004) Inhibition of AP-1 and neoplastic transformation by fresh apple peel extract. J Biol Chem 279:10670–10676PubMedGoogle Scholar
  68. 68.
    Kolb WP, Granger GA (1968) Lymphocyte in vitro cytotoxicity: characterization of human lymphotoxin. Proc Natl Acad Sci U S A 61:1250–1255PubMedGoogle Scholar
  69. 69.
    Brynskov J, Foegh P, Pedersen G, Ellervik C, Kirkegaard T, Bingham A et al (2002) Tumour necrosis factor α converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease. Gut 51:37–43PubMedGoogle Scholar
  70. 70.
    Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487–501PubMedGoogle Scholar
  71. 71.
    Wadsworth TL, Koop DR (1999) Effects of the wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages. Biochem Pharmacol 57:941–949PubMedGoogle Scholar
  72. 72.
    Kawada N, Seki S, Inoue M, Kuroki T (1998) Effect of antioxidants, resveratrol, quercetin, and N-acetylcysteine, on the functions of cultured rat hepatic stellate cells and Kupffer cells. Hepatology 27:1265–1274PubMedGoogle Scholar
  73. 73.
    Lambert JD, Sang S, Hong J, Yang CS (2010) Anticancer and anti-inflammatory effects of cysteine metabolites of the green tea polyphenol, (−)-epigallocatechin-3-gallate. J Agric Food Chem 58:10016–10019PubMedGoogle Scholar
  74. 74.
    Abe Y, Hashimoto SHU, Horie T (1999) Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res 39:41–47PubMedGoogle Scholar
  75. 75.
    Singh S, Natarajan K, Aggarwal BB (1996) Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a potent inhibitor of nuclear transcription factor-kappa B activation by diverse agents. J Immunol 157:4412–4420PubMedGoogle Scholar
  76. 76.
    Eugui EM, DeLustro B, Rouhafza S, Ilnicka M, Lee SW, Wilhelm R et al (1994) Some antioxidants inhibit, in a co-ordinate fashion, the production of tumor necrosis factor-alpha, IL-beta, and IL-6 by human peripheral blood mononuclear cells. Int Immunol 6:409–422PubMedGoogle Scholar
  77. 77.
    Habtemariam S (2000) Natural inhibitors of tumour necrosis factor-alpha production, secretion and function. Planta Med 66:303–313PubMedGoogle Scholar
  78. 78.
    Natarajan K, Manna SK, Chaturvedi MM, Aggarwal BB (1998) Protein tyrosine kinase inhibitors block tumor necrosis factor-induced activation of nuclear factor-kappaB, degradation of IkappaBalpha, nuclear translocation of p65, and subsequent gene expression. Arch Biochem Biophys 352:59–70PubMedGoogle Scholar
  79. 79.
    Zi X, Mukhtar H, Agarwal R (1997) Novel cancer chemopreventive effects of a flavonoid antioxidant silymarin: inhibition of mRNA expression of an endogenous tumor promoter TNF alpha. Biochem Biophys Res Commun 239:334–339PubMedGoogle Scholar
  80. 80.
    Fujiki H, Suganuma M, Okabe S, Sueoka N, Komori A, Sueoka E et al (1998) Cancer inhibition by green tea. Mutat Res 402:307–310PubMedGoogle Scholar
  81. 81.
    Kawaguchi K, Kikuchi S, Hasegawa H, Maruyama H, Morita H, Kumazawa Y (1999) Suppression of lipopolysaccharide-induced tumor necrosis factor-release and liver injury in mice by naringin. Eur J Pharmacol 368:245–250PubMedGoogle Scholar
  82. 82.
    Cho JY, Park J, Yoo ES, Yoshikawa K, Baik KU, Lee J et al (1998) Inhibitory effect of lignans from the rhizomes of Coptis japonica var. dissecta on tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW264.7 cells. Arch Pharm Res 21:12–16PubMedGoogle Scholar
  83. 83.
    Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JWM et al (1989) The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 320:265–271PubMedGoogle Scholar
  84. 84.
    O’Donnell VB, Spycher S, Azzi A (1995) Involvement of oxidants and oxidant-generating enzyme(s) in tumour-necrosis-factor-alpha-mediated apoptosis: role for lipoxygenase pathway but not mitochondrial respiratory chain. Biochem J 310:133–141PubMedGoogle Scholar
  85. 85.
    Habtemariam S (1997) Flavonoids as inhibitors or enhancers of the cytotoxicity of tumor necrosis factor-alpha in L-929 tumor cells. J Nat Prod 60:775–778PubMedGoogle Scholar
  86. 86.
    Marnett LJ, Kalgutkar AS (1999) Cyclooxygenase 2 inhibitors: discovery, selectivity and the future. Trends Pharmacol Sci 20:465–469PubMedGoogle Scholar
  87. 87.
    Subbaramaiah K, Dannenberg AJ (2003) Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 24:96–102PubMedGoogle Scholar
  88. 88.
    Kim EJ, Raval AP, Perez-Pinzon MA (2008) Preconditioning mediated by sublethal oxygen-glucose deprivation-induced cyclooxygenase-2 expression via the signal transducers and activators of transcription 3 phosphorylation. J Cereb Blood Flow Metab 28:1329–1340PubMedGoogle Scholar
  89. 89.
    Baumann J, von Bruchhausen F, Wurm G (1980) Flavonoids and related compounds as inhibition of arachidonic acid peroxidation. Prostaglandins 20:627–639PubMedGoogle Scholar
  90. 90.
    Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T, Inoue H et al (1998) Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Biol Chem 273:21875–21882PubMedGoogle Scholar
  91. 91.
    Plummer SM, Holloway KA, Manson MM, Munks RJ, Kaptein A, Farrow S et al (1999) Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene 18:6013–6020PubMedGoogle Scholar
  92. 92.
    Mutoh M, Takahashi M, Fukuda K, Matsushima-Hibiya Y, Mutoh H, Sugimura T et al (2000) Suppression of cyclooxygenase-2 promoter-dependent transcriptional activity in colon ­cancer cells by chemopreventive agents with a resorcin-type structure. Carcinogenesis 21:959–963PubMedGoogle Scholar
  93. 93.
    Gerhäuser C, Klimo K, Heiss E, Neumann I, Gamal-Eldeen A, Knauft J et al (2003) Mechanism-based in vitro screening of potential cancer chemopreventive agents. Mutat Res 523–524:163–172PubMedGoogle Scholar
  94. 94.
    Montrose DC, Horelik NA, Madigan JP, Stoner GD, Wang L-S, Bruno RS et al (2011) Anti-inflammatory effects of freeze-dried black raspberry powder in ulcerative colitis. Carcinogenesis 32:343–350PubMedGoogle Scholar
  95. 95.
    Bodet C, Chandad F, Grenier D (2007) Cranberry components inhibit interleukin-6, interleukin-8, and prostaglandin E2 production by lipopolysaccharide-activated gingival fibroblasts. Eur J Oral Sci 115:64–70PubMedGoogle Scholar
  96. 96.
    Lau FC, Bielinski DF, Joseph JA (2007) Inhibitory effects of blueberry extract on the production of inflammatory mediators in lipopolysaccharide-activated BV2 microglia. J Neurosci Res 85:1010–1017PubMedGoogle Scholar
  97. 97.
    Adams LS, Seeram NP, Aggarwal BB, Takada Y, Sand D, Heber D (2006) Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem 54:980–985PubMedGoogle Scholar
  98. 98.
    Kundu JK, Na H-K, Chun K-S, Kim Y-K, Lee SJ, Lee SS et al (2003) Inhibition of phorbol ester-induced COX-2 expression by epigallocatechin gallate in mouse skin and cultured human mammary epithelial cells. J Nutr 133:3805S–3810SPubMedGoogle Scholar
  99. 99.
    Sharma S, Katiyar S (2010) Dietary grape seed proanthocyanidins inhibit UVB-induced cyclooxygenase-2 expression and other inflammatory mediators in UVB-exposed skin and skin tumors of SKH-1 hairless mice. Pharm Res 27:1092–1102PubMedGoogle Scholar
  100. 100.
    Lau TY, Leung LK (2006) Soya isoflavones suppress phorbol 12-myristate 13-acetate-induced COX-2 expression in MCF-7 cells. Br J Nutr 96:169–176PubMedGoogle Scholar
  101. 101.
    Shumway BS, Kresty LA, Larsen PE, Zwick JC, Lu B, Fields HW et al (2008) Effects of a topically applied bioadhesive berry gel on loss of heterozygosity indices in premalignant oral lesions. Clin Cancer Res 14:2421–2430PubMedGoogle Scholar
  102. 102.
    Mallery SR, Zwick JC, Pei P, Tong M, Larsen PE, Shumway BS et al (2008) Topical application of a bioadhesive black raspberry gel modulates gene expression and reduces cyclooxygenase 2 protein in human premalignant oral lesions. Cancer Res 68:4945–4957PubMedGoogle Scholar
  103. 103.
    Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X et al (2011) Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci U S A 108:4129–4134PubMedGoogle Scholar
  104. 104.
    Schneider I, Bucar F (2005) Lipoxygenase inhibitors from natural plant sources. Part 1: medicinal plants with inhibitory activity on arachidonate 5-lipoxygenase and 5-lipoxygenase[sol]cyclooxygenase. Phytother Res 19:81–102PubMedGoogle Scholar
  105. 105.
    Kröncke F, Kolb B (1998) Inducible nitric oxide synthase in human diseases. Clin Exp Immunol 113:147–156PubMedGoogle Scholar
  106. 106.
    Bogdan C (2001) Nitric oxide and the regulation of gene expression. Trends Cell Biol 11:66–75PubMedGoogle Scholar
  107. 107.
    Kleinert H, Wallerath T, Fritz G, Ihrig-Biedert I, Rodriguez-Pascual F, Geller DA et al (1998) Cytokine induction of NO synthase II in human DLD-1 cells: roles of the JAK-STAT, AP-1 and NF-κB-signaling pathways. Br J Pharmacol 125:193–201PubMedGoogle Scholar
  108. 108.
    Lin Y-L, Lin J-K (1997) (−)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide-induced activity of transcription factor nuclear factor-kappaB. Mol Pharmacol 52:465–472PubMedGoogle Scholar
  109. 109.
    Ippoushi K, Azuma K, Ito H, Horie H, Higashio H (2003) [6]-Gingerol inhibits nitric oxide synthesis in activated J774.1 mouse macrophages and prevents peroxynitrite-induced oxidation and nitration reactions. Life Sci 73:3427–3437PubMedGoogle Scholar
  110. 110.
    Tsai S-H, Lin-Shiau S-Y, Lin J-K (1999) Suppression of nitric oxide synthase and the down-regulation of the activation of NFκB in macrophages by resveratrol. Br J Pharmacol 126:673–680PubMedGoogle Scholar
  111. 111.
    Chan MM-Y, Huang H-I, Fenton MR, Fong D (1998) In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties. Biochem Pharmacol 55:1955–1962PubMedGoogle Scholar
  112. 112.
    Chen YH, Dai HJ, Chang HP (2003) Suppression of inducible nitric oxide production by indole and isothiocyanate derivatives from Brassica plants in stimulated macrophages. Planta Med 69:696–700PubMedGoogle Scholar
  113. 113.
    Chen Y-C, Shen S-C, Lee W-R, Hou W-C, Yang L-L, Lee TJF (2001) Inhibition of nitric oxide synthase inhibitors and lipopolysaccharide induced inducible NOS and cyclooxygenase-2 gene expressions by rutin, quercetin, and quercetin pentaacetate in RAW 264.7 macrophages. J Cell Biochem 82:537–548PubMedGoogle Scholar
  114. 114.
    Zhang X, Huang H, Yang T, Ye Y, Shan J, Yin Z et al (2010) Chlorogenic acid protects mice against lipopolysaccharide-induced acute lung injury. Injury 41:746–752PubMedGoogle Scholar
  115. 115.
    Tedeschi E, Menegazzi M, Yao Y, Suzuki H, Förstermann U, Kleinert H (2004) Green tea inhibits human inducible nitric-oxide synthase expression by down-regulating signal transducer and activator of transcription-1alpha activation. Mol Pharmacol 65:111–120PubMedGoogle Scholar
  116. 116.
    Kim OK, Murakami A, Nakamura Y, Ohigashi H (1998) Screening of edible Japanese plants for nitric oxide generation inhibitory activities in RAW 264.7 cells. Cancer Lett 125:199–207PubMedGoogle Scholar
  117. 117.
    Choi SE, Park KH, Han BH, Jeong MS, Seo SJ, Lee DI et al (2011) Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by phenolic compounds from roots of rhododendron mucronulatum. Phytother Res 25:1301–1305Google Scholar
  118. 118.
    Madrigal-Carballo S, Rodríguez G, Sibaja M, Reed JD, Vila AO, Molina F (2009) Chitosomes loaded with cranberry proanthocyanidins attenuate the bacterial lipopolysaccharide-induced expression of iNOS and COX-2 in raw 264.7 macrophages. J Liposome Res 19:189–196PubMedGoogle Scholar
  119. 119.
    Poulose SM, Fisher DR, Larson J, Bielinski DF, Rimando AM, Carey AN et al (2012) Anthocyanin-rich açai (Euterpe oleracea Mart.) fruit pulp fractions attenuate inflammatory stress signaling in mouse brain BV-2 microglial cells. J Agric Food Chem 60:1084–1093PubMedGoogle Scholar
  120. 120.
    Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266PubMedGoogle Scholar
  121. 121.
    Lin WW, Karin M (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117:1175–1183PubMedGoogle Scholar
  122. 122.
    Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ et al (1987) Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49:729–739PubMedGoogle Scholar
  123. 123.
    Grivennikov SI, Karin M (2010) Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21:11–19PubMedGoogle Scholar
  124. 124.
    Arlt A, Vorndamm J, Müerköster S, Yu H, Schmidt WE, Fölsch UR et al (2002) Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines. Cancer Res 62:910–916PubMedGoogle Scholar
  125. 125.
    Klein B, Zhang X, Jourdan M, Content J, Houssiau F, Aarden L et al (1989) Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 73:517–526PubMedGoogle Scholar
  126. 126.
    Voorzanger N, Touitou R, Garcia E, Delecluse H-J, Rousset F, Joab I et al (1996) Interleukin (IL)-10 and IL-6 are produced in vivo by non-Hodgkin’s lymphoma cells and act as cooperative growth factors. Cancer Res 56:5499–5505PubMedGoogle Scholar
  127. 127.
    Okamoto M, Kawamata H, Kawai K, Oyasu R (1995) Enhancement of transformation in vitro of a nontumorigenic rat urothelial cell line by interleukin 6. Cancer Res 55:4581–4585PubMedGoogle Scholar
  128. 128.
    Landi S, Moreno V, Gioia-Patricola L, Guino E, Navarro M, de Oca J et al (2003) Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. Cancer Res 63:3560–3566PubMedGoogle Scholar
  129. 129.
    Luca M, Huang S, Gershenwald JE, Singh RK, Reich R, Bar-Eli M (1997) Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. Am J Pathol 151:1105–1113PubMedGoogle Scholar
  130. 130.
    Feng Y-H, Zhu Y-N, Liu J, Ren Y-X, Xu J-Y, Yang Y-F et al (2004) Differential regulation of resveratrol on lipopolysaccharide-stimulated human macrophages with or without IFN-γ ­pre-priming. Int Immunopharmacol 4:713–720PubMedGoogle Scholar
  131. 131.
    Cho JW, Lee KS, Kim CW (2007) Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. Int J Mol Med 19:469–474PubMedGoogle Scholar
  132. 132.
    Choi YH, Yan GH (2009) Ellagic Acid attenuates immunoglobulin E-mediated allergic response in mast cells. Biol Pharm Bull 32:1118–1121PubMedGoogle Scholar
  133. 133.
    Gao X, Liu K, Huang F, Zhang D, Guo X, Wang M et al (2013) Positive and negative regulation of insulin action by genistein in the endothelium. J Nutr Biochem 24(1):222–230PubMedGoogle Scholar
  134. 134.
    Kang M, Park K, Seo J, Kim H (2011) Lycopene inhibits IL-6 expression in cerulein-stimulated pancreatic acinar cells. Genes Nutr 6:117–123PubMedGoogle Scholar
  135. 135.
    Bhutani M, Pathak AK, Nair AS, Kunnumakkara AB, Guha S, Sethi G et al (2007) Capsaicin is a novel blocker of constitutive and interleukin-6-inducible STAT3 activation. Clin Cancer Res 13:3024–3032PubMedGoogle Scholar
  136. 136.
    Ahmed S, Marotte H, Kwan K, Ruth JH, Campbell PL, Rabquer BJ et al (2008) Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production. Proc Natl Acad Sci U S A 105:14692–14697PubMedGoogle Scholar
  137. 137.
    Sueoka N, Suganuma M, Sueoka E, Okabe S, Matsuyama S, Imai K et al (2001) A new function of green tea: prevention of lifestyle-related diseases. Ann N Y Acad Sci 928:274–280PubMedGoogle Scholar
  138. 138.
    Kim H, Kim J, Song H, Park K, Mun K-C, Ha E (2011) Grape seed proanthocyanidin extract inhibits interleukin-17-induced interleukin-6 production via MAPK pathway in human pulmonary epithelial cells. Naunyn Schmiedebergs Arch Pharmacol 383:555–562PubMedGoogle Scholar
  139. 139.
    Kim YH, Choi EM (2009) Stimulation of osteoblastic differentiation and inhibition of interleukin-6 and nitric oxide in MC3T3-E1 cells by pomegranate ethanol extract. Phytother Res 23:737–739PubMedGoogle Scholar
  140. 140.
    Zhou Z, Nair MG, Claycombe KJ (2012) Synergistic inhibition of interleukin-6 production in adipose stem cells by tart cherry anthocyanins and atorvastatin. Phytomedicine 19:878–881PubMedGoogle Scholar
  141. 141.
    Huang M-T, Liu Y, Ramji D, Lo C-Y, Ghai G, Dushenkov S et al (2006) Inhibitory effects of black tea theaflavin derivatives on 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and arachidonic acid metabolism in mouse ears. Mol Nutr Food Res 50:115–122PubMedGoogle Scholar
  142. 142.
    Wang LS, Arnold M, Huang YW, Sardo C, Seguin C, Martin E et al (2011) Modulation of genetic and epigenetic biomarkers of colorectal cancer in humans by black raspberries: a phase I pilot study. Clin Cancer Res 17:598–610PubMedGoogle Scholar
  143. 143.
    Stoner GD (2009) Foodstuffs for preventing cancer: the preclinical and clinical development of berries. Cancer Prev Res (Phila) 2:187–194Google Scholar
  144. 144.
    Mentor-Marcel RA, Bobe G, Sardo C, Wang LS, Kuo CT, Stoner G et al (2012) Plasma cytokines as potential response indicators to dietary freeze-dried black raspberries in colorectal cancer patients. Nutr Cancer 64:820–825PubMedGoogle Scholar
  145. 145.
    Sardo C, Kitzmiller J, Apseloff G, Harris R, Roe D, Stoner G et al. Reducing postprandial inflammation with black raspberries: a pilot study in older obese and overweight men ­(submitted for publication)Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Hematology and Oncology, Department of MedicineMedical College of WisconsinMilwaukeeUSA

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