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Modulatory Properties of Various Natural Chemopreventive Agents on the Activation of NF-κB Signaling Pathway

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Abstract

Purpose. To study and compare effects of selected natural chemopreventive agents on the transcription activation of nuclear factor-kappa B (NF-κB) in human HT-29 colon cancer cells.

Methods. The natural chemopreventive compounds isothiocyanates (ITCs) found in cruciferous vegetables, flavonoids found in green tea, resveratrol (RES) and procyanidin dimers found in red wine, and curcumin (CUR) found in turmeric curry food were examined in this study. HT-29 cells were stably transfected with NF-κB luciferase construct, and stable clones were selected. One of the clones, HT-29 N9 cells, was selected and treated with various concentrations of the natural chemopreventive agents and subsequently challenged with NF-κB stimulator lipopolysaccharide (LPS), and the luciferase activities were measured. Western blot analysis of phosphorylated IκBα was performed after treatments with the natural chemopreventive agents. The effects of these agents on cell viability and apoptosis were also evaluated by a nonradioactive cell proliferation MTS assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-arboxymethoxyphenyl)-2-(4-sulfo- phenyl)-2H-tetrazolium, inner salt], Trypan blue staining, and caspase assay.

Results. Treatments with the natural chemopreventive compounds resulted in different responses in the NF-κB-luciferase assay. ITCs such as phenethyl isothiocyanate (PEITC), sulforaphane (SUL), allyl isothiocyanate (AITC), and curcumin (CUR) strongly inhibited LPS-induced NF-κB-luciferase activations, whereas RES increased activation at lower dose, but inhibited activation at higher dose, and tea flavonoids and procyanidin dimers had little or no effects. ITCs, CUR, (-)-epigallocatechin-3-gallate (EGCG), and RES reduced LPS-induced IκBα phosphorylation. Furthermore, in the MTS assay, PEITC, SUL, and CUR also potently inhibited cell growth. Caspase-3 activity was induced by chemopreventive compounds, however, the kinetics of caspase-3 activation varied between these compounds within the 48-h time period.

Conclusions. These results suggest that natural chemopreventive agents have differential biological functions on the signal transduction pathways in the colon and/or colon cancer.

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References

  1. D. M. Parkin, P. Pisani, and J. Ferlay. Global cancer statistics. CA Cancer J. Clin. 49:33-64 (1999).

    Google Scholar 

  2. D. K. Rex. Screening for colon cancer and evaluation of chemoprevention with coxibs. J. Pain Symptom Manage. 23:S41-S50 (2002).

    Google Scholar 

  3. P. A. Baeuerle and D. Baltimore. NF-kappa B: ten years after. Cell 87:13-20 (1996).

    Google Scholar 

  4. A. M. Kamat and D. L. Lamm. Chemoprevention of urological cancer. J. Urol. 161:1748-1760 (1999).

    Google Scholar 

  5. J. D. Potter. Colon cancer—do the nutritional epidemiology, the gut physiology and the molecular biology tell the same story? J. Nutr. 123:418-423 (1993).

    Google Scholar 

  6. U. Siebenlist, G. Franzoso, and K. Brown. Structure, regulation and function of NF-kappa B. Annu. Rev. Cell Biol. 10:405-455 (1994).

    Google Scholar 

  7. S. Ghosh, M. J. May, and E. B. Kopp. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16:225-260 (1998).

    Google Scholar 

  8. J. M. Muller, H. W. Ziegler-Heitbrock, and P. A. Baeuerle. Nuclear factor kappa B, a mediator of lipopolysaccharide effects. Immunobiology 187:233-256 (1993).

    Google Scholar 

  9. M. Karin and Y. Ben-Neriah. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu. Rev. Immunol. 18:621-663 (2000).

    Google Scholar 

  10. Y. Yamamoto and R. B. Gaynor. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J. Clin. Invest. 107:135-142 (2001).

    Google Scholar 

  11. X. H. Li, X. Fang, and R. B. Gaynor. Role of IKKgamma/nemo in assembly of the Ikappa B kinase complex. J. Biol. Chem. 276:4494-4500 (2001).

    Google Scholar 

  12. S. Amit and Y. Ben-Neriah. NF-kappaB activation in cancer: a challenge for ubiquitination-and proteasome-based therapeutic approach. Semin. Cancer Biol. 13:15-28 (2003).

    Google Scholar 

  13. P. J. Barnes and M. Karin. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336:1066-1071 (1997).

    Google Scholar 

  14. V. R. Baichwal and P. A. Baeuerle. Activate NF-kappa B or die? Curr. Biol. 7:R94-R96 (1997).

    Google Scholar 

  15. A. N. Kong, R. Yu, V. Hebbar, C. Chen, E. Owuor, R. Hu, R. Ee, and S. Mandlekar. Signal transduction events elicited by cancer prevention compounds. Mutat. Res. 480–481:231-241 (2001).

    Google Scholar 

  16. S. Gupta, N. H. Purcell, A. Lin, and S. Sen. Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac hypertrophy. J. Cell Biol. 159:1019-1028 (2002).

    Google Scholar 

  17. N. H. Purcell, G. Tang, C. Yu, F. Mercurio, J. A. DiDonato, and A. Lin. Activation of NF-kappa B is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes. Proc. Natl. Acad. Sci. U. S. A. 98:6668-6673 (2001).

    Google Scholar 

  18. J. W. Pierce, R. Schoenleber, G. Jesmok, J. Best, S. A. Moore, T. Collins, and M. E. Gerritsen. Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J. Biol. Chem. 272:21096-21103 (1997).

    Google Scholar 

  19. N. A. Thornberry and Y. Lazebnik. Caspases: enemies within. Science 281:1312-1316 (1998).

    Google Scholar 

  20. G. Guhr and P. A. Lachance. Role of phytochemicals in chronic disease prevention. In P. A. Lachance (ed.), Designer Foods III. Garlic, Soy and Licorice., Food & Nutrition Press, Trumbull, 1997, pp. 311-357.

    Google Scholar 

  21. T. A. Shapiro, J. W. Fahey, K. L. Wade, K. K. Stephenson, and P. Talalay. Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol. Biomarkers Prev. 7:1091-1100 (1998).

    Google Scholar 

  22. E. Heiss, C. Herhaus, K. Klimo, H. Bartsch, and C. Gerhauser. Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J. Biol. Chem. 276:32008-32015 (2001).

    Google Scholar 

  23. E. J. Patten and M. J. DeLong. Temporal effects of the detoxification enzyme inducer, benzyl isothiocyanate: activation of c-Jun N-terminal kinase prior to the transcription factors AP-1 and NFkappaB. Biochem. Biophys. Res. Commun. 257:149-155 (1999).

    Google Scholar 

  24. M. T. Huang, T. Lysz, T. Ferraro, T. F. Abidi, J. D. Laskin, and A. H. Conney. Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Res. 51:813-819 (1991).

    Google Scholar 

  25. A. Kumar, S. Dhawan, N. J. Hardegen, and B. B. Aggarwal. Curcumin (diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation. Biochem. Pharmacol. 55:775-783 (1998).

    Google Scholar 

  26. S. Singh and B. B. Aggarwal. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane). J. Biol. Chem. 270:24995-25000 (1995).

    Google Scholar 

  27. S. S. Han, Y. S. Keum, H. J. Seo, and Y. J. Surh. Curcumin suppresses activation of NF-kappaB and AP-1 induced by phorbol ester in cultured human promyelocytic leukemia cells. J. Biochem. Mol. Biol. 35:337-342 (2002).

    Google Scholar 

  28. C. Jobin, C. A. Bradham, M. P. Russo, B. Juma, A. S. Narula, D. A. Brenner, and R. B. Sartor. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J. Immunol. 163:3474-3483 (1999).

    Google Scholar 

  29. S. M. Plummer, K. A. Holloway, M. M. Manson, R. J. Munks, A. Kaptein, S. Farrow, and L. Howells. 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 18:6013-6020 (1999).

    Google Scholar 

  30. S. Philip and G. C. Kundu. Osteopontin induces nuclear factor kappa B-mediated promatrix metalloproteinase-2 activation through I kappa B alpha/IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways. J. Biol. Chem. 278:14487-14497 (2003).

    Google Scholar 

  31. S. Banerjee, C. Bueso-Ramos, and B. B. Aggarwal. Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in ratsby resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res. 62:4945-4954 (2002).

    Google Scholar 

  32. D. I. Cho, N. Y. Koo, W. J. Chung, T. S. Kim, S. Y. Ryu, S. Y. Im, and K. M. Kim. Effects of resveratrol-related hydroxystilbenes on the nitric oxide production in macrophage cells: structural requirements and mechanism of action. Life Sci. 71:2071-2082 (2002).

    Google Scholar 

  33. X. Gao, Y. X. Xu, N. Janakiraman, R. A. Chapman, and S. C. Gautam. Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production. Biochem. Pharmacol. 62:1299-1308 (2001).

    Google Scholar 

  34. S. K. Manna, A. Mukhopadhyay, and B. B. Aggarwal. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J. Immunol. 164:6509-6519 (2000).

    Google Scholar 

  35. S. H. Tsai, S. Y. Lin-Shiau, and J. K. Lin. Suppression of nitric oxide synthase and the down-regulation of the activation of NFkappaB in macrophages by resveratrol. Br. J. Pharmacol. 126:673-680 (1999).

    Google Scholar 

  36. C. S. Yang, P. Maliakal, and X. Meng. Inhibition of carcinogenesis by tea. Annu. Rev. Pharmacol. Toxicol. 42:25-54 (2002).

    Google Scholar 

  37. Y. C. Park, G. Rimbach, C. Saliou, G. Valacchi, and L. Packer. Activity of monomeric, dimeric, and trimeric flavonoids on NO production, TNF-alpha secretion, and NF-kappaB-dependent gene expression in RAW 264.7 macrophages. FEBS Lett. 465:93-97 (2000).

    Google Scholar 

  38. C. Saliou, G. Rimbach, H. Moini, L. McLaughlin, S. Hosseini, J. Lee, R. R. Watson, and L. Packer. Solar ultraviolet-induced erythema in human skin and nuclear factor-kappa-B-dependent gene expression in keratinocytes are modulated by a French maritime pine bark extract. Free Radic. Biol. Med. 30:154-160 (2001).

    Google Scholar 

  39. G. Y. Yang, J. Liao, K. Kim, E. J. Yurkow, and C. S. Yang. Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols. Carcinogenesis 19:611-616 (1998).

    Google Scholar 

  40. H. Kamata, T. Manabe, S. Oka, K. Kamata, and H. Hirata. Hydrogen peroxide activates IkappaB kinases through phosphorylation of serine residues in the activation loops. FEBS Lett. 519:231-237 (2002).

    Google Scholar 

  41. H. Nakagawa, M. Wachi, J. T. Woo, M. Kato, S. Kasai, F. Takahashi, I. S. Lee, and K. Nagai. Fenton reaction is primarily involved in a mechanism of (-)-epigallocatechin-3-gallate to induce osteoclastic cell death. Biochem. Biophys. Res. Commun. 292:94-101 (2002).

    Google Scholar 

  42. J. Li, H. Zhou, Q. Cai, and G. Xiao. Activation of NF-kappaB and apoptosis of intestinal epithelial cells induced by hydrogen peroxide. Chin. J. Traumatol. 5:209-213 (2002).

    Google Scholar 

  43. C. Chen, G. Shen, V. Hebbar, R. Hu, E. D. Owuor, and A. N. Kong. Epigallocatechin-3-gallate-induced stress signals in HT-29 human colonadenocarcinoma cells. Carcinogenesis 24:1369-1378 (2003).

    Google Scholar 

  44. A. Simon, D. P. Allais, J. L. Duroux, J. P. Basly, S. Durand-Fontanier, and C. Delage. Inhibitory effect of curcuminoids on MCF-7 cell proliferation and structure-activity relationships. Cancer Lett. 129:111-116 (1998).

    Google Scholar 

  45. H. Ahsan, N. Parveen, N. U. Khan, and S. M. Hadi. Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. Chem. Biol. Interact. 121:161-175 (1999).

    Google Scholar 

  46. M. Salucci, L. A. Stivala, G. Maiani, R. Bugianesi, and V. Vannini. Flavonoids uptake and their effect on cell cycle of human colon adenocarcinoma cells (Caco2). Br. J. Cancer 86:1645-1651 (2002).

    Google Scholar 

  47. S. M. Kuo. Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells. Cancer Lett. 110:41-48 (1996).

    Google Scholar 

  48. S. K. Manna, A. Mukhopadhyay, N. T. Van, and B. B. Aggarwal. Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J. Immunol. 163:6800-6809 (1999).

    Google Scholar 

  49. S. Simizu, M. Takada, K. Umezawa, and M. Imoto. Requirement of caspase-3(-like) protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs. J. Biol. Chem. 273:26900-26907 (1998).

    Google Scholar 

  50. H. S. Samaha, G. J. Kelloff, V. Steele, C. V. Rao, and B. S. Reddy. Modulation of apoptosis by sulindac, curcumin, phenylethyl-3-methylcaffeate, and 6-phenylhexyl isothiocyanate: apoptotic index as a biomarker in colon cancer chemoprevention and promotion. Cancer Res. 57:1301-1305 (1997).

    Google Scholar 

  51. R. Yu, S. Mandlekar, K. J. Harvey, D. S. Ucker, and A. N. Kong. Chemopreventive isothiocyanates induce apoptosis and caspase-3-likeprotease activity. Cancer Res. 58:402-408 (1998).

    Google Scholar 

  52. R. Hu, B. R. Kim, C. Chen, V. Hebbar, and A. N. Kong. The roles of JNK and apoptotic signaling pathways in PEITC-mediated responses in human HT-29 colon adenocarcinoma cells. Carcinogenesis 24:1361-1367 (2003).

    Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854

    Woo-Sik Jeong, In-Wha Kim, Rong Hu & Ah-Ng Tony Kong

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  1. Woo-Sik Jeong
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Correspondence to Ah-Ng Tony Kong.

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Jeong, WS., Kim, IW., Hu, R. et al. Modulatory Properties of Various Natural Chemopreventive Agents on the Activation of NF-κB Signaling Pathway. Pharm Res 21, 661–670 (2004). https://doi.org/10.1023/B:PHAM.0000022413.43212.cf

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