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.
Similar content being viewed by others
References
Brennan MJ. Endocrinology in cancer of the breast. Status and prospects.Am J Clin Pathol. 1975;64:797–809.
Lee JS, Surh YJ. Nrf2 as a novel molecular target for chemoprevention.Cancer Lett. 2005;224:171–184.
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.
Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression.J Mammary Gland Biol Neoplasia. 1998;3:49–61.
Philip M, Rowley DA, Schreiber H. Inflammation as a tumor promoter in cancer induction.Semin Cancer Biol. 2004;14:433–439.
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.
Balkwill F, Charles KA, Mantovani A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease.Cancer Cell. 2005;7:211–217.
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.
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.
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.
Liu RH. Potential synergy of phytochemicals in cancer prevention: mechanism of action.J Nutr. 2004;134:3479S-3485S.
Mohandas KM, Desai DC. Epidemiology of digestive tract cancers in India, V: large and small bowel.Indian J Gastroenterol. 1999;18:118–121.
Ammon HP, Wahl MA. Pharmacology of Curcuma longa.Planta Med. 1991;57:1–7.
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.
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.
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.
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.
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.
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.
Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies.Anticancer Res. 2003;23:363–398.
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.
Pollard JW. Tuniour-educated macrophages promote tumour progression and metastasis.Nat Rev Cancer. 2004;4:71–78.
Sreejayan MN, Rao MN. Nitric oxide scavenging by curcuminoids.J Pharm Pharmacol. 1997;49:105–117.
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.
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.
de Visser KE, Coussens LM. The interplay between innate and adaptive immunity regulates cancer development.Cancer Immunol Immunother. 2005;54:1143–1152.
Yadav VS, Mishra KP, Singh DP, Mehrotra S, Singh VK. Immunomodulatory effects of curcumin.Immunopharmacol Immunotoxicol. 2005;27:485–497.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Mann JR, DuBois RN. Cyclooxygenase-2 and gastrointestinal cancer.Cancer J. 2004;10:145–152.
Prescott SM. Is cyclooxygenase-2 the alpha and the omega in cancer?J Clin Invest. 2000;105:1511–1513.
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.
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.
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.
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.
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.
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.
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.
John A, Tuszynski G. The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis.Pathol Oncol Res. 2001;7:14–23.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Fujie H, Moriya K, Shintani Y, et al. Frequent beta-catenin aberration in human hepatocellular carcinoma.Hepatol Res. 2001;20:39–51.
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.
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.
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.
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.
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.
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.
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.
Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer.Biochim Biophys Acta. 2003;1653:1–24.
Author information
Authors and Affiliations
Corresponding author
Additional information
Published: July 7, 2006