Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Suppression of Protein Kinase C and Nuclear Oncogene Expression as Possible Action Mechanisms of Cancer Chemoprevention by Curcumin

  • Lin, Jen-Kun (Institutes of Biochemistry, College of Medicine, National Taiwan University)
  • Published : 2004.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

Curcumin (diferuloylmethane) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animal models. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase; and an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C(PKC), EGF(Epidermal growth factor)-receptor tyrosine kinase and LĸB kinase. Subsequently, curcumin inhibits the activation of NF(nucleor factor)KB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs and iNOS. It is proposed that curcumin may suppress tumor promotion through blocking signal transduction path-ways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, while the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins playa pivotal role in the regulation of several basic cellular processes including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of ubiquitin-proteasome pathway. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin and that these compounds subsequently were converted to monoglucuronide conjugates. These results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are the major metabolites of curcumin in mice, rats and humans.

Keywords

References

  1. Anto, R. J., Venkatraman, M.,and Karunagaran, D., Inhibition of NF${\kappa}$B sensitizes A431 cells to epidermal growth factor-inducedapoptosis, whereas its activation by ectopic expressio of ReiA confers resistance. J. Biol. Chem., 278, 25490-25498(2003) https://doi.org/10.1074/jbc.M301790200
  2. Armstrong, B. and Doll, R., Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int. J. Cancer, 15, 617-631 (1975) https://doi.org/10.1002/ijc.2910150411
  3. Bharti, A. C., Donato, N., Singh, S., and Aggarwal, B. B. Curcumin down-regulates the constitutive activation of nuclear factor ${\kappa}$B and $I{\kappa}B{\alpha}$ kinase in human multiple myeloma cells leading to suppression of proliferation and induction of apoptosis. Blood, 101, 1053-1062 (2003) https://doi.org/10.1182/blood-2002-05-1320
  4. Chan, M. M. Y., Huang, H. I., Fenton, M. R., and Fong, D., In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with antiinflammatory properties. Biochem Pharmacol, 55, 1955-1962(1998) https://doi.org/10.1016/S0006-2952(98)00114-2
  5. Chen, C. M. and Fang, H. C., Chemical Analysis of the active principles of Curcuma species, in: Modern Treatise on Chinese Herbal Medicines, C.Y. Sung (ed), The Institute of Pharmaceutical Sciences, Medical Academia, Beijing, China, Vol. III,pp 95-105, (1997)
  6. Chen, W. J. and lin, J. K., Induction of G1 arrestand apoptosis in human Jarkat T cells by pentagalloylglucose through inhibiting proteasome activityand elevating p27, p21 and bax protein. J. Biol. Chem., 279, 13496-13525 (2004) https://doi.org/10.1074/jbc.M212390200
  7. Chen, Y. C., Kuo,T.C., Lin-Shiau, S. Y., and Lin, J. K., Induction of HSP70 gene expression by modulation of calciumion and cellular p53 protein by curcumin in colorectal carcinoma cells. Mol Carcinogenesis 17, 224-234 (1996) https://doi.org/10.1002/(SICI)1098-2744(199612)17:4<224::AID-MC6>3.0.CO;2-D
  8. Cheng, A. L., Hsu, C. H., Lin, J. K., Hsu, M. M., Ho, Y. F., Shen, T. S., Ko, J. Y., Lin, J. T., Lin, B. R., Ming-Shiang, W., Yu, H. S., Jee, S. H., Chen, G. S., Chen. T. M., Chen, C. A., Lai, M. K., Pu, Y. S., Pan, M. H., Wang, Y. J., Tsai, C. C., and Hsieh, C. Y., Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high risk or pre-malignant lesion. Anticancer Res., 21,2895-2900 (2001)
  9. Chuang, S. E., Kuo, M. L., Hsu, C. H., Chen, C. R., Lin, J. K., Lai, G. M., Hsieh, C. Y., .and Cheng, A. L., Curcumincontaining diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis, 21, 331-335(2000) https://doi.org/10.1093/carcin/21.2.331
  10. Chun, K. S., Keum, Y. S., Han, S. S., Song, Y. S., Kim, S. H., and Surh, Y. J., Curcumin inhibits phorbal ester-induced expression of cyclooxygenase-2 in mouse skin through expression of extracellular signal-regulated kinase activity and NFK8 activation. Carcinogenesis, 24, 1515-1524 (2003) https://doi.org/10.1093/carcin/bgg107
  11. Conney, A. H., Lou, V. R., Xie, J. G., Osawa, T., Newmark, H. L., Liu, Y., Chang, R. L., and Huang, M. T., Some perspectives on dietary inhibition of carcinogenesis: Studies with curcumin and tea. Proc. Soc. Exp. Biol. Med., 216, 234-245 (1997) https://doi.org/10.3181/00379727-216-44173
  12. Conney, A. H., Lysz, T., Ferraro, T, Abidi, T. F., Manchand, P. S., Laskin, J. D., and Huang, M. T, Inhibitory effect of curcumin and some related dietary compounds on tumor promotion and arachidonic acid metabolism in mouse skin. Adv Enzyme Regul, 31,385-389 (1991) https://doi.org/10.1016/0065-2571(91)90025-H
  13. Deeb, D., Xu, Y. X., Jiang, H., Gao, X., Janakiraman, N., Chapman, R. A, and Gautam, S. C., Curcumin enhances tumor necrosis factor-related apoptosis-inducing-ligandinduced apoptosis in LNCaP prostate cancer cells. Mol. Cancer Ther., 2, 95-103 (2003)
  14. Dinkova-Kostova, A., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Vamamoto, M., and Talalay, P, Direct evidence that sulfhydryl groups of Keap 1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and antioxidants. Proc. Nat. Acad. Sci. U.S.A., 99, 11908-11913 (2002) https://doi.org/10.1073/pnas.172398899
  15. Dinkova-Kostova, A and Talalay, P., Relation of structure of curcumin alalogs to their potencies as inducers of phase 2 detoxification enzymes. Carcinogenesis, 20, 911-914 (1999) https://doi.org/10.1093/carcin/20.5.911
  16. Gopalakrishna, R. and Gundimeda,U., Antioxidant regulating protein kinase C in cancer prevention. J. Nutr., 132, 3819s-3823s (2002)
  17. Gopalakrishna, R. and Jaken, S., Protein kinase C signaling and oxidative stress. Free Radic. Biol. Med., 28, 1349-1361 (2000) https://doi.org/10.1016/S0891-5849(00)00221-5
  18. Haystead, T A., Sim, A. T., and Carling, D., Effects of the tumor promoter okadaic acid on intracellular protein phosphoryla-tion and metabolism. Nature, 337, 78-81 (1989) https://doi.org/10.1038/337078a0
  19. Huang, M. T, Smart, R. C., Wong, C. Q., and Conney, A. H. Inhibitory effect of curcumin, chlorogenic acid, caffeic acid and ferulic acid on tumor promotion in mouse skin by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res, 48, 5941-5946 (1988)
  20. Huang, M. T., Lysz, T, Ferraro,T., Abidi, T F., Laskin, J. D., and Conney, A H., Inhibitory effects of curcumin in vivo lipoxy-genase and cyclooxygenase activities in mouse epidermis. Cancer Res, 51,813-819 (1991)
  21. Huang, M. T., Wang, Z. V., Georgiadis, C. A., Laskin, J. D., and Conney, A. H., Inhibitory effect of curcumin on tumor initiation by benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene. Carcinogenesis, 13, 947-954 (1992) https://doi.org/10.1093/carcin/13.6.947
  22. Huang, M. T., Lou, Y. R., Ma, w., Newmark, H. L., Reuhl, K. R.,and Conney, A H., Inhibitory effect of dietary curcumin on forestomach, duodenal and colon carcinogenesis in mice. Cancer Res, 54, 5841-5847 (1994)
  23. Huang, M. T, Ma, W., Lu, V. P., Chang, R. L., Fischer, C., Manchand, P S., Newmark, H. L., and Conney,A. H., Effects of curcumin, demethoxycurcumin,bisdemethoxycurcumin and tetrahydrocurcumin on TPA-induced tumor promotion. Carcinogenesis, 16, 2493-2497 (1995) https://doi.org/10.1093/carcin/16.10.2493
  24. Huang, M. T, Ma, W., Ven,P., Xie, J. G., Han, J., Fenkel, K,D. Grunberger, K D.,and Conney, A. H., Inhibitory effects of topical application of low doses of curcumin on TPA-induced tumor promotion and oxidized DNA bases in mouse epidermis. Carcinogenesis, 18,83-88 (1997) https://doi.org/10.1093/carcin/18.1.83
  25. Huang, T. S., Lee, S. C., and Lin, J. K., Suppression of $\sigma$-Jun/ AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc. Natl Acad Sci. U.S.A., 88, 5292-5296 (1991) https://doi.org/10.1073/pnas.88.12.5292
  26. Inano, H., Onoda, M., Inafuku, N., Kubota, M., Kamada, Y., Osawa, T, Kobayashi, H., and Wakabayashi, K,Potent protective action of curcumin on radiation-induced initiation of mammary tumorigenesis in rats. Carcinogenesis, 21, 1835-1841 (2000) https://doi.org/10.1093/carcin/21.10.1835
  27. Ireson, C., Jones, D. J., Orr, S., Coughtrie, M. W, Hoocock, D. J., Williams, M. L., Farmer, P. B., Steward, W. P., and Gescher, A, Metabolism of the Cancer Chemopreventive agent curcumin in human and rat intestine. Cancer Epidermiol. Biomarkers Prev., 11, 105-111 (2002)
  28. Ireson, C., Orr, S., Jones, D. J., Verschoyle, R., Lim, C. K., Luo, J. L., Howells, L., Plummer, S., Jukes, R., Williams, M., Steward, W. P.,and Gescher, A., Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production. Cancer Res., 61, 1058-1064 (2001)
  29. Jana, N. R., Dikshit, P., Goswami, A., and Nukina, w., Inhibition of proteasomal function by curcumin induces apoptosis through mitochondrial pathway. J. Biol. Chem., 279, 11680-11685 (2004) https://doi.org/10.1074/jbc.M310369200
  30. Jiang, M. C., Yang-Ven, H. F., Ven, J. J., and Lin, J. K., Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines. Nutr Cancer, 26, 111-120 (1996) https://doi.org/10.1080/01635589609514468
  31. Korutla, L., Cheung, J. Y., Mendelsohn, J., Kumar, R., Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin. Carcinogenesis, 16, 1741-1745 (1995) https://doi.org/10.1093/carcin/16.8.1741
  32. Korutla, L. and Kumar, R., Inhibitory effects of curcumin on epidermal growth factor receptor kinase activity in A431 cellls. Biochim BiophysActa, 1224,597-600 (1994) https://doi.org/10.1016/0167-4889(94)90299-2
  33. Kunchandy, E. and Rao, M. N. A., Oxygen scavenging activity of curcumin. Int. J. Pharm., 38, 239-240 (1990)
  34. Kuo, M. L., Huang, T S., and Lin, J. K., Curcumin, an anti-oxidant and anti-tumor promoter, induced apoptosis in human leukemia cells. Biochim Biophys Acta, 1317, 95-100 (1996) https://doi.org/10.1016/S0925-4439(96)00032-4
  35. Lin, J. K., Huang, T. S., C. A Shih, C. A., and Liu, J. L. Molecular mechanism of action of curcumin, in:Food Phyto-Chemicals for Cancer Prevention II. ACS Symposium Series 547, C. THo, T Osawa, M. T Huang, and R. T Rosen (eds), Amercian Chemical Society, Washington, D. C., pp. 196-203 (1994)
  36. Lin, J. K. and Lin-Shiau, S. Y, Cancer chemoprevention by curcumin. Proc. Natl. Sci. Counc. Repub. China B, 25, 59-66 (2001)
  37. Lin, J. K. and Shih, C. A, Inhibitory effect of curcumin on xanthine dehydrogenase/oxidase induced by TPA in NIH 3T3 cells. Carcinogenesis, 15, 1717-1721 (1994) https://doi.org/10.1093/carcin/15.8.1717
  38. Lin, L. I., Ke, Y. F, Ko,Y. C., and Lin J. K., Curcumin inhibits SK-Hep-1 hepatocellular carcinoma cell invasion in vitro and suppresses matrix metalloproteinase 9 secretion. Oncology, 55, 349-353 (1998) https://doi.org/10.1159/000011876
  39. Liu, J. Y, Lin, S. J., and Lin, J. K., Inhibitory effects of curcumin on protein kinase C activity induced by TPA in NIH 3T3 cells. Carcinogenesis, 14, 857-861 (1993) https://doi.org/10.1093/carcin/14.5.857
  40. Lu, Y. P., Cahng, R. L., Lou, Y R., Huang, M. T, Newmark, H. L., Heuhl, K. R., and Conney, A. H., Effect of curcumin on TPA- and ultraviolet B light induced expression of ${\sigma}$-jun and ${\sigma}$-fos in JB6 cells and in mouse epidermis. Carcinogenesis, 15, 2363-2370 (1994) https://doi.org/10.1093/carcin/15.10.2363
  41. Manson, M. M., Gescher, A, Hudson, E. A, Plummer, S. M., Squires, M. S., and Prigent, S. A., Blocking and Suppressing mechanisms of chemoprevention by dietary constituents. Toxicol. Lett., 112-113, 499-505 (2000) https://doi.org/10.1016/S0378-4274(99)00211-8
  42. Motterlin, R., Foresti, R., Bassi, R., and Green, C. J., Curcumin, an antioxidant And anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radic. Bioi. Med., 28,1303-1312 (2000) https://doi.org/10.1016/S0891-5849(00)00294-X
  43. Natarajan, C. and Bright, J. J., Curcumin inhibits experimental allergic encephalomyelitis by pathway in T lymphocytes. J. Immunol., 169, 6506-6513 (2002)
  44. Naujokat, C., and Hoffmann, S. Role and function of 26S proteasome in proliferation and apoptosis. Lab. Invst., 82, 965-980 (2002) https://doi.org/10.1097/01.LAB.0000022226.23741.37
  45. Pan, M. H., Chang, W L., Lin-Shiau, S. Y., Ho, C. T, and Lin, J. K., Induction of apoptosis by garcinol and curcumin through cytochrome c release and activation of caspases in human leukemia HL-60 cells. J. Agric. Food Chem., 49, 1464-1474(2001) https://doi.org/10.1021/jf001129v
  46. Pan, M. H., Huang, T. M., and Lin, J. K., Biotransformation of curcumin through reduction and glucuronizationm in mice. Drug Metab Disposit, 27, 486-494 (1999)
  47. Phillip, S., Bulbule, A, and Kundu, G. C., Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear tactor-${\kappa}$B ediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells. J. Biol. Chem., 276, 44926-44935 (2001) https://doi.org/10.1074/jbc.M103334200
  48. Phillip, S. and Kandu, G. C., Osteopontin induces nuclear factor ${\kappa}$B-mediated promatrix metalloproteinase-2 activation through I${\kappa}$B${\alpha}$/IKK signaling pathways and curcumin down regulate these pathways. J. Biol. Chem., 278, 14487-14497 (2003) https://doi.org/10.1074/jbc.M207309200
  49. Phillips, R. L., Role of life-style and dietary habits in risk of cancer among seventh-day Adventists. Cancer Res., 35, 3513-3522 (1975)
  50. Quiles, J. L., Dolores Mesa, M., Ramirez-Tortosa, C. L., Anguilera, C. M., Battino, M., Gil, A., and Carmen Ramirez-Tortosa, M., Curcuma longa extract supplementation induces oxidative stress and attenuates aortic fatty streak develop-ment in rabbits. ArterioscJer. Thromb. Vase. Biol., 22, 1225-1231 (2002) https://doi.org/10.1161/01.ATV.0000020676.11586.F2
  51. Rao, C. V., Riven, Simi, A B., and Reddy, B. S., Chemopreven-tion of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res, 55, 259-266 (1995)
  52. Scapagnini, G., Foresti, R., Calabrese, V., Giuffrida Stella, A M., Green, C. J., and Motterlin, R., Caffeic acid phenethyl ester and curcumin: A novel class of heme oxygenase-1 inducers. Mol. Pharmacol., 3, 554-561 (2002)
  53. Sharma, R. A., Ireson, C. R., Verschoyle, R. D., Hill, K. A, Williams, M. L.,Leuratti, C., Manson, M. M., Marett, L. J., Steward, W P., and Gescher, A, Effect of dietary curcurnln on glutathione S-transferase and malondialdehyde-DNA adducts in rat liver and colon mucosa: Relationship with drug levels. Clin. Cancer Res., 7,1452-1458 (2001)
  54. Shih, C. A and Lin, J. K., Inhibition of 8-hydroxydeoxyguano-sine formation by curcumin in mouse fibrblast cells. Carcinogenesis, 14, 709-712 (1994) https://doi.org/10.1093/carcin/14.4.709
  55. Singh, S. V., Hu, X., Srivastava, S. K., Singh, M., Xia, H., Orchard, J. L., and Zaren, H. A, Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin. Carcinogenesis, 19, 13576-1760 (1998)
  56. Singh, S., and Aggarwal, B. B., Activation of transcription factor NF$\kappa$B is suppressing by curcumin. J. Biol. Chem., 270, 24995-25000 (1995) https://doi.org/10.1074/jbc.270.42.24995
  57. Sporn, M. B. and Roberts, A. B., Peptide growth factors are multifunctional. Nature, 332, 217-219 (1988) https://doi.org/10.1038/332217a0
  58. Squires, M. S., Hidson, E. A, Howells, L., Sale, S., Houghton, C. E., Jones, J. L., Fox, L. H., Dickens, M., Prigent, S. A., and Manson, M. M., Relevance of mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells. Biachem. Pharmacol., 65, 361-376 (2003) https://doi.org/10.1016/S0006-2952(02)01517-4
  59. Sreejayan Rao, M.N.A. Curcuminoids as potent inhibitors of lipid peroxidation. J. Pharm. Pharmacol.,46, 1013-1016 (1994) https://doi.org/10.1111/j.2042-7158.1994.tb03258.x
  60. Subramanian, M., Sreejayan Rao, M. N. A, Devasagyam, T. P. A, and Singh, B. B., Diminution of singlet oxygen induced DNA-damage by curcumin and related antioxidants. Mutat Res, 311, 249-255 (1994) https://doi.org/10.1016/0027-5107(94)90183-X
  61. Sun, L. and Carpenter, G., Epidermal growth factor activation of NF$\kappa$B is mediated through I$\kappa$B$\alpha$ degradation and intracellular free calcium. Oncogene, 16, 2095-2102 (1998) https://doi.org/10.1038/sj.onc.1201731
  62. Woo, J. H., Kim, Y. H., Choi, Y. J., Kim, D. G., Lee, K. S., Hae, J. H., Min, D. S., Chang, J. S., Jeong, Y. J., Lee, Y. S., Park, J. W., and Kwon, J. K., Molecular mechanisms of curcumin-induced cytotoxicity: Induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis, 24, 1199-1208 (2003) https://doi.org/10.1093/carcin/bgg082