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Multiple molecular targets in cancer chemoprevention by curcumin

Abstract

Carcinogenesis encompasses 3 closely associated stages: initiation, progression, and promotion. Phytochemicals are nonnutritive components of plants that are currently being studied in chemoprevention of various diseases for their pleiotropic effects and nontoxicity. Cancer chemoprevention involves the use of either natural or synthetic chemicals to prevent the initiation, promotion, or progression of cancer. Curcumin is the active constituent of turmeric, which is widely used as a spice in Indian cooking. It has been shown to posses anti-inflammatory, antioxidant, and antitumor properties. Curcumin has also been shown to be beneficial in all 3 stages of carcinogenesis. Much of its beneficial effect is found to be due to its inhibition of the transcription factor nuclear factor kappa B (NF-kappaB) and subsequent inhibition of proinflammatory pathways. This review summarizes the inhibition of NF-kappaB by curcumin and describes the recently identified molecular targets of curcumin. It is hoped that continued research will lead to development of curcumin as an anticancer agent.

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References

  1. Brennan MJ. Endocrinology in cancer of the breast. Status and prospects.Am J Clin Pathol. 1975;64:797–809.

    CAS  Article  PubMed  Google Scholar 

  2. Lee JS, Surh YJ. Nrf2 as a novel molecular target for chemoprevention.Cancer Lett. 2005;224:171–184.

    CAS  Article  PubMed  Google Scholar 

  3. Surh YJ, Kundu JK, Na HK, Lee JS. Redox-sensitive transcription factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals.J Nutr. 2005;135:2993S-3001S.

    CAS  PubMed  Google Scholar 

  4. Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression.J Mammary Gland Biol Neoplasia. 1998;3:49–61.

    CAS  Article  PubMed  Google Scholar 

  5. Philip M, Rowley DA, Schreiber H. Inflammation as a tumor promoter in cancer induction.Semin Cancer Biol. 2004;14:433–439.

    CAS  Article  PubMed  Google Scholar 

  6. Cross MJ, Claesson-Welsh L. FGF and VEGF function in angiogenesis: signalling pathways, biological responses and therapeutic inhibition.Trends Pharmacol Sci. 2001;22:201–207.

    CAS  Article  PubMed  Google Scholar 

  7. Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease.Cancer Cell. 2005;7:211–217.

    CAS  Article  PubMed  Google Scholar 

  8. Owen JL, Iragavarapu-Charyulu V, Lopez DM. T cell-derived matrix metalloproteinase-9 in breast cancer: friend or foe?Breast Dis. 2004;20:145–153.

    CAS  Article  PubMed  Google Scholar 

  9. Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing life and death—a new approach to cancer therapy.J Clin Invest. 2005;115:2625–2632.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids).Fed Proc. 1976;35:1332–1338.

    CAS  PubMed  Google Scholar 

  11. Liu RH. Potential synergy of phytochemicals in cancer prevention: mechanism of action.J Nutr. 2004;134:3479S-3485S.

    CAS  PubMed  Google Scholar 

  12. Mohandas KM, Desai DC. Epidemiology of digestive tract cancers in India, V: large and small bowel.Indian J Gastroenterol. 1999;18:118–121.

    CAS  PubMed  Google Scholar 

  13. Ammon HP, Wahl MA. Pharmacology of Curcuma longa.Planta Med. 1991;57:1–7.

    CAS  Article  PubMed  Google Scholar 

  14. Chen A, Xu J, Johnson AC. Curcumin inhibits human colon cancer cell growth by suppressing gene expression of epidermal growth factor receptor through reducing the activity of the transcription factor Egr-1.Oncogene. 2006;25:278–287.

    PubMed  Google Scholar 

  15. Perkins S, Verschoyle RD, Hill K, et al. Chem opreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis.Cancer Epidemiol Biomarkers Prev. 2002;11:535–540.

    CAS  PubMed  Google Scholar 

  16. Huang MT, Lou YR, Ma W, Newmark HL, Reuhl KR, Conney AH. Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice.Cancer Res. 1994;54:5841–5847.

    CAS  PubMed  Google Scholar 

  17. Singh SV, Hu X, Srivastava SK, et al. Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin.Carcinogenesis. 1998;19:1357–1360.

    CAS  Article  PubMed  Google Scholar 

  18. Dorai T, Cao YC, Dorai B, Buttyan R, Katz AE. Therapeutic potential of curcumin in human prostate cancer, III: curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo.Prostate. 2001;47:293–303.

    CAS  Article  PubMed  Google Scholar 

  19. Choudhuri T, Pal S, Das T, Sa G. Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner.J Biol Chem. 2005;280:20059–20068.

    CAS  Article  PubMed  Google Scholar 

  20. Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies.Anticancer Res. 2003;23:363–398.

    CAS  PubMed  Google Scholar 

  21. Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions.Anticancer Res. 2001;21:2895–2900.

    CAS  PubMed  Google Scholar 

  22. Pollard JW. Tuniour-educated macrophages promote tumour progression and metastasis.Nat Rev Cancer. 2004;4:71–78.

    CAS  Article  PubMed  Google Scholar 

  23. Sreejayan MN, Rao MN. Nitric oxide scavenging by curcuminoids.J Pharm Pharmacol. 1997;49:105–117.

    CAS  Article  PubMed  Google Scholar 

  24. Brouet I, Ohshima H. Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages.Biochem Biophys Res Commun. 1995;206:533–540.

    CAS  Article  PubMed  Google Scholar 

  25. Pan MH, Lin-Shiau SY, Lin JK. Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down-regulation of IkappaB kinase and NFkappaB activation in macrophages.Biochem Pharmacol. 2000;60:1665–1676.

    CAS  Article  PubMed  Google Scholar 

  26. de Visser KE, Coussens LM. The interplay between innate and adaptive immunity regulates cancer development.Cancer Immunol Immunother. 2005;54:1143–1152.

    Article  PubMed  Google Scholar 

  27. Yadav VS, Mishra KP, Singh DP, Mehrotra S, Singh VK. Immunomodulatory effects of curcumin.Immunopharmacol Immunotoxicol. 2005;27:485–497.

    CAS  Article  PubMed  Google Scholar 

  28. Grandjean-Laquerriere A, Gangloff SC, Le Naour R, Trentesaux C, Hornebeck W, Guenounou M. Relative contribution of NF-kappaB and AP-1 in the modulation by curcumin and pyrrolidine dithiocarbamate of the UVB-induced cytokine expression by keratinocytes.Cytokine. 2002;18:168–177.

    CAS  Article  PubMed  Google Scholar 

  29. Feng R, Lu Y, Bowman LL, Qian Y, Castranova V, Ding M. Inhibition of activator protein-1, NF-kappaB, and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid.J Biol Chem. 2005;280:27888–27895.

    CAS  Article  PubMed  Google Scholar 

  30. Takada Y, Bhardwaj A, Potdar P, Aggarwal BB. Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation.Oncogene. 2004;23:9247–2958.

    CAS  PubMed  Google Scholar 

  31. Firozi PF, Aboobaker VS, Bhattacharya RK. Action of curcumin on the cytochrome P450-system catalyzing the activation of aflatoxin B1.Chem Biol Interact. 1996;100:41–51.

    CAS  Article  PubMed  Google Scholar 

  32. Iqbal M, Sharma SD, Okazaki Y, Fujisawa M, Okada S. Dietary supplementation of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice: possible role in protection against chemical carcinogenesis and toxicity.Pharmacol Toxicol. 2003;92:33–38.

    CAS  Article  PubMed  Google Scholar 

  33. Okazaki Y, Iqbal M, Okada S. Suppressive effects of dietary curcumin on the increased activity of renal ornithine decarboxylase in mice treated with a renal carcinogen, ferric nitrilotriacetate.Biochim Biophys Acta. 2005;1740:357–366.

    CAS  Article  PubMed  Google Scholar 

  34. Tanaka T, Makita H, Ohnishi M, et al. Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis by dietary curcumin and hesperidin: comparison with the protective effect of beta-carotene.Cancer Res. 1994;54:4653–4659.

    CAS  PubMed  Google Scholar 

  35. Motterlini R, Foresti R, Bassi R, Green CJ. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress.Free Radic Biol Med. 2000;28:1303–1312.

    CAS  Article  PubMed  Google Scholar 

  36. Hill M, Pereira V, Chauveau C, et al. Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase.FASEB J. 2005;19:1957–1968.

    CAS  Article  PubMed  Google Scholar 

  37. Andreadi CK, Howells LM, Atherfold PA, Manson MM. Involvement of Nrf2, p38, B-Raf, and nuclear factor-{kappa}B, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols.Mol Pharmacol. 2006;69:1033–1040.

    CAS  PubMed  Google Scholar 

  38. Balogun E, Hoque M, Gong P, et al. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element.Biochem J. 2003;371:887–895.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements.Biochem Biophys Res commun. 1997;236:313–322.

    CAS  Article  PubMed  Google Scholar 

  40. Pool-Zobel B, Veeriah S, Bohmer FD. Modulation of xenobiotic metabolising enzymes by anticarcinogens-focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis.Mutat Res. 2005;591:74–92.

    CAS  Article  PubMed  Google Scholar 

  41. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit.Nat Rev Cancer. 2002;2:301–310.

    CAS  Article  PubMed  Google Scholar 

  42. Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-kappaB and IkappB proteins: implications in cancer and inflammation.Trends Biochem Sci. 2005;30:43–52.

    CAS  Article  PubMed  Google Scholar 

  43. Greten FR, Eckmann L, Greten TF, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.Cell. 2004;118:285–296.

    CAS  Article  PubMed  Google Scholar 

  44. Aggarwal S, Takada Y, Singh S, Myers JN, Aggarwal BB. Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling.Int J Cancer. 2004;111:679–692.

    CAS  Article  PubMed  Google Scholar 

  45. Notarbartolo M, Poma P, Perri D, Dusonchet L, Cervello M, D’Alessandro N. Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression.Cancer Lett. 2005;224:53–65.

    CAS  Article  PubMed  Google Scholar 

  46. Shishodia S, Amin HM, Lai R, Aggarwal BB. Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma.Biochem Pharmacol. 2005;70:700–713.

    CAS  Article  PubMed  Google Scholar 

  47. Mann JR, DuBois RN. Cyclooxygenase-2 and gastrointestinal cancer.Cancer J. 2004;10:145–152.

    CAS  Article  PubMed  Google Scholar 

  48. Prescott SM. Is cyclooxygenase-2 the alpha and the omega in cancer?J Clin Invest. 2000;105:1511–1513.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Claria J, Romano M. Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways. Impact on inflammation and cancer.Curr Pharm Des. 2005;11:3431–3447.

    CAS  Article  PubMed  Google Scholar 

  50. Kim JH, Lee KW, Lee MW, Lee HJ, Kim SH, Surh YJ. Hirsutenone inhibits phorbol ester-induced upregulation of COX-2 and MMP-9 in cultured human mammary epithelial cells: NF-kappaB as a potential molecular target.FEBS Lett. 2006;580:385–392.

    CAS  Article  PubMed  Google Scholar 

  51. Du B, Jiang L, Xia Q, Zhong L. Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human colon cancer cell line HT-29.Chemotherapy. 2006;52:23–28.

    CAS  Article  PubMed  Google Scholar 

  52. Atsumi T, Murakami Y, Shibuya K, Tonosaki K, Fujisawa S. Induction of cytotoxicity and apoptosis and inhibition of cyclooxygenase-2 gene expression, by curcumin and its analog, alphadiisoengenol.Anticancer Res. 2005;25:4029–4036.

    CAS  PubMed  Google Scholar 

  53. Goel A, Boland CR, Chauhan DP. Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells.Cancer Lett. 2001;172:111–118.

    CAS  Article  PubMed  Google Scholar 

  54. Surh YJ, Chun KS, Cha HH, et al. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation.Mutat Res. 2001;480–481:243–268.

    Article  PubMed  Google Scholar 

  55. Lee KW, Kim JH, Lee HJ, Surh YJ. Curcumin inhibits phorbol ester-induced up-regulation of cyclooxygenase-2 and matrix metalloproteinase-9 by blocking ERK1/2 phosphorylation and NF-kappaB transcriptional activity in MCF10A human breast epithelial cells.Antioxid Redox Signal. 2005;7:1612–1620.

    CAS  Article  PubMed  Google Scholar 

  56. John A, Tuszynski G. The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis.Pathol Oncol Res. 2001;7:14–23.

    CAS  Article  PubMed  Google Scholar 

  57. Woo MS, Jung SH, Kim SY, et al. Curcumin suppresses phorbol ester-induced matrix metalloproteinase-9 expression by inhibiting the PKC to MAPK signaling pathways in human astroglioma cells.Biochem Biophys Res Commun. 2005;335:1017–1025.

    CAS  Article  PubMed  Google Scholar 

  58. Aggarwal BB, Shishodia S, Takada Y, et al. Curcum in suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice.Clin Cancer Res. 2005;11:7490–7498.

    CAS  Article  PubMed  Google Scholar 

  59. O’Hanlon DM, Fitzsimons H, Lynch J, Tormey S, Malone C, Given HF. Soluble adhesion molecules (E-selectin, ICAM-1, and VCAM-1) in breast carcinoma.Eur J Cancer. 2002;38:2252–2257.

    Article  PubMed  Google Scholar 

  60. Lee CW, Lin WN, Lin CC, et al. Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-alpha in human tracheal smooth muscle cells: involvement of MAPKs, NF-kappaB, p300, and histone acetylation.J Cell Physiol. 2006;207:174–186.

    CAS  Article  PubMed  Google Scholar 

  61. Hour TC, Chen J, Huang CY, Guan JY, Lu SH, Pu YS. Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21(WAF1/CIP1) and C/EBPbeta expressions and suppressing NF-kappaB activation.Prostate. 2002;51:211–218.

    CAS  Article  PubMed  Google Scholar 

  62. Philip S, Bulbule A, Kundu GC. Matrix metalloproteinase-2: mechanism and regulation of NF-kappaB-mediated activation and its role in cell motility and ECM-invasion.Glycoconj J. 2004;21:429–441.

    CAS  Article  PubMed  Google Scholar 

  63. Donati V, Boldrini L, Dell’Omodarme M, et al. Osteopontin expression and prognostic significance in non-small cell lung cancer.Clin Cancer Res. 2005;11:6459–6465.

    CAS  Article  PubMed  Google Scholar 

  64. Chelouche-Lev D, Miller CP, Tellez C, Ruiz M, Bar-Eli M, Price JE. Different signalling pathways regulate VEGF and IL-8 expression in breast cancer: implications for therapy.Eur J Cancer. 2004;40:2509–2518.

    CAS  Article  PubMed  Google Scholar 

  65. Li L, Aggarwal BB, Shishodia S, Abbruzzese J, Kurzrock R. Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis.Cancer. 2004;101:2351–2362.

    CAS  Article  PubMed  Google Scholar 

  66. Hidaka H, Ishiko T, Furuhashi T, et al. Curcumin inhibits interleukin 8 production and enhances interleukin 8 receptor expression on the cell surface: impact on human pancreatic carcinoma cell growth by autocrine regulation.Cancer. 2002;95:1206–1214.

    CAS  Article  PubMed  Google Scholar 

  67. Thaloor D, Singh AK, Sidhu GS, Prasad PV, Kleinman HK, Maheshwari RK. Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by curcumin.Cell Growth Differ. 1998;9:305–312.

    CAS  PubMed  Google Scholar 

  68. Singh AK, Sidhu GS, Deepa T, Maheshwari RK. Curcumin inhibits the proliferation and cell cycle progression of human umbilical vein endothelial cell.Cancer Lett. 1996;107:109–115.

    CAS  Article  PubMed  Google Scholar 

  69. Morin PJ, Sparks AB, Korinek V, et al. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.Science. 1997;275:1787–1790.

    CAS  Article  PubMed  Google Scholar 

  70. Fujie H, Moriya K, Shintani Y, et al. Frequent beta-catenin aberration in human hepatocellular carcinoma.Hepatol Res. 2001;20:39–51.

    CAS  Article  PubMed  Google Scholar 

  71. Woo DK, Kim HS, Lee HS, Kang YH, Yang HK, Kim WH. Altered expression and mutation of beta-catenin gene in gastric carcinomas and cell lines.Int J Cancer. 2001;95:108–113.

    CAS  Article  PubMed  Google Scholar 

  72. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly.Science. 1996;272:1023–1026.

    CAS  Article  PubMed  Google Scholar 

  73. Yoshida R, Kimura N, Harada Y, Ohuchi N. The loss of E-cadherin, alpha-and beta-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer.Int J Oncol. 2001;18:513–520.

    CAS  PubMed  Google Scholar 

  74. Kildal W, Risberg B, Abeler VM, et al. Beta-catenin expression, DNA ploidy and clinicopathological features in ovarian cancer: a study in 253 patients.Eur J Cancer. 2005;41:1127–1134.

    CAS  Article  PubMed  Google Scholar 

  75. Park CH, Hahm ER, Park S, Kim HK, Yang CH. The inhibitory mechanism of curcumin and its derivative against beta-catenin/Tcf signaling.FEBS Lett. 2005;579:2965–2971.

    CAS  Article  PubMed  Google Scholar 

  76. Jaiswal AS, Marlow BP, Gupta N, Narayan S. Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells.Oncogene. 2002;21:8414–8427.

    CAS  Article  PubMed  Google Scholar 

  77. Mahmoud NN, Carothers AM, Grunberger D, et al. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis.Carcinogenesis. 2000;21:921–927.

    CAS  Article  PubMed  Google Scholar 

  78. Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer.Biochim Biophys Acta. 2003;1653:1–24.

    CAS  PubMed  Google Scholar 

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Correspondence to Radha K. Maheshwari.

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Published: July 7, 2006

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Thangapazham, R.L., Sharma, A. & Maheshwari, R.K. Multiple molecular targets in cancer chemoprevention by curcumin. AAPS J 8, E443 (2006). https://doi.org/10.1208/aapsj080352

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Keywords

  • Curcumin
  • NF-kappaB
  • Nrf2
  • β-catenin