Abstract
Inhibition of defined molecular steps of tumorigenesis by natural nontoxic compounds may be an efficient means to tackle the population cancer burden. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively nontoxic plant-derived polyphenol. This review considers the following properties of curcumin: anticancer effects in animal model systems; metabolism; biological structure and pharmacokinetics; biological properties implicated in chemoprevention; antioxidant properties; influences upon Phase I and II carcinogen-metabolizing enzymes; signal transduction properties and the neoplastic phenotype; apoptosis evasion, cell proliferation, de-differentiation, migration and invasion and clinical studies. This review will summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention.
Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.
Bibliography
- 1 Sharma OP: Antioxidant activity of curcumin and related compounds. Biochem. Pharmacol.25,1811–1812 (1976).Crossref, Medline, CAS, Google Scholar
- 2 Subramanian M, Sreejayan Rao MN, Devasagayam TP, Singh BB: Diminution of singlet oxygen-induced DNA damage by curcumin and related antioxidants. Mutat. Res.311,249–255 (1994).Crossref, Medline, CAS, Google Scholar
- 3 Chopra RN, Chopra IC, Handa KL, Kapur LD: Indigenous drugs of India. In Calcutta,325–327 (1958).Google Scholar
- 4 Huang MT, Smart RC, Wong CQ, Conney AH: 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).Seminal study of curcumin inhibition of tumor promotion and arachidonic acid-mediated edema.Medline, CAS, Google Scholar
- 5 Huang MT, Lysz T, Ferraro T, Abidi TF, Laskin JD, Donney AH: Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Res.51,813–819 (1991).Important study showing curcumin inhibition of arachidonic acid metabolism and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion.Medline, CAS, Google Scholar
- 6 Conney AH, Lysz T, Ferraro T et al.: Inhibitory effect of curcumin and some related dietary compounds on tumor promotion and arachidonic acid metabolism in mouse skin. Adv. Enzyme Regul.31,385–396 (1991).Crossref, Medline, CAS, Google Scholar
- 7 Rao CV, Rivenson A, Simi B, Reddy BS: Chemoprevention of colon carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound. Cancer Res.55,259–266 (1995).Important study showing curcumin inhibition of azoxymethane-induced colorectal tumorigenesis and modulation of arachidonic acid metabolism.Medline, CAS, Google Scholar
- 8 Reddy BS: Studies with the azoxymethane-rat preclinical model for assessing colon tumor development and chemoprevention. Environ. Mol. Mutagen44,26–35 (2004).Crossref, Medline, CAS, Google Scholar
- 9 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.54,5841–5847 (1994).Interesting study showing curcumin inhibition of gastrointestinal tumourigenesis induced by various chemical mutagens.Medline, CAS, Google Scholar
- 10 Ikezaki S, Nishikawa A, Furukawa F et al.: Chemopreventive effects of curcumin on glandular stomach carcinogenesis induced by N-methyl-N´-nitro-N-nitrosoguanidine and sodium chloride in rats. Anticancer Res.21,3407–3411 (2001).Medline, CAS, Google Scholar
- 11 Conney AH: Enzyme induction and dietary chemicals as approaches to cancer chemoprevention: the seventh DeWitt S. Goodman Lecture. Cancer Res.63,7005–7031 (2003).Medline, CAS, Google Scholar
- 12 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 β-carotene. Cancer Res.54,4653–4659 (1994).Medline, CAS, Google Scholar
- 13 Huang MT, Newmark HL, Frenkel K: Inhibitory effects of curcumin on tumorigenesis in mice. J. Cell Biochem. Suppl.27,26–34 (1997).Crossref, Medline, CAS, Google Scholar
- 14 Sindhwani P, Hampton JA, Baig MM, Keck R, Selman SH: Curcumin prevents intravesical tumor implantation of the MBT-2 tumor cell line in C3H mice. J. Urol.166,1498–1501 (2001).Crossref, Medline, CAS, Google Scholar
- 15 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. Prostate47,293–303 (2001).Crossref, Medline, CAS, Google Scholar
- 16 Holder GM, Plummer JL, Ryan AJ: The metabolism and excretion of curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat. Xenobiotica8, 761–768 (1978).Crossref, Medline, CAS, Google Scholar
- 17 Ireson C, Orr S, Jones DJ et al.: 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).Important study of hepatic biotransformation of curcumin and biological activity of metabolites. Demonstrated that unmetabolized curcumin but not metabolites, effectively inhibits COX-2 activity.Medline, CAS, Google Scholar
- 18 Ireson CR, Jones DJ, Orr S et al.: Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiol. Biomarkers Prev.11,105–111 (2002).Interesting study showing metabolism of curcumin by intestinal as well as hepatic microsomes and the metabolic role of phenol sulfotransferase isoenzymes.Medline, CAS, Google Scholar
- 19 Sharma RA, Euden SA, Platton SL et al.: Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin. Cancer Res.10,6847–6854 (2004).Important study demonstrating patient tolerance of high dose oral curcumin which achieved pharmacological inhibition of prostaglandin E2.Crossref, Medline, CAS, Google Scholar
- 20 Troll W, Frenkel K, Teebor G: Free oxygen radicals: necessary contributors to tumor promotion and cocarcinogenesis. Princess Takamatsu Symp.14,207–218 (1983).Interesting review which defines the role of free oxygen radicals in tumor promotion.Medline, CAS, Google Scholar
- 21 Frenkel K: Oxidation of DNA bases by tumor promoter-activated processes. Environ. Health Perspect.81,45–54 (1989).Crossref, Medline, CAS, Google Scholar
- 22 Tonnesen HH, Greenhill JV: Studies on curcumin and curcuminoids. XXII: curcumin as a reducing agent and as a radical scavenger. Int. J. Pharm.87,79–87 (1992).Crossref, Google Scholar
- 23 Reddy AC, Lokesh BR: Studies on the inhibitory effects of curcumin and eugenol on the formation of reactive oxygen species and the oxidation of ferrous iron. Mol. Cell Biochem.137,1–8 (1994).Crossref, Medline, CAS, Google Scholar
- 24 Donatus IA, Sardjoko, Vermeulen NP: Cytotoxic and cytoprotective activities of curcumin. Effects on paracetamol-induced cytotoxicity, lipid peroxidation and glutathione depletion in rat hepatocytes. Biochem. Pharmacol.39,1869–1875 (1990).Crossref, Medline, CAS, Google Scholar
- 25 Zhang F, Altorki NK, Mestre JR, Subbaramaiah K, Dannenberg AJ: Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol ester-treated human gastrointestinal epithelial cells. Carcinogenesis20,445–451 (1999).Crossref, Medline, CAS, Google Scholar
- 26 Plummer SM, Holloway KA, Manson MM et al.: Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-κB activation via the NIK/IKK signalling complex. Oncogene18,6013–6020 (1999).First report showing that induction of COX-2 by colon tumor promoters is inhibited by curcumin, by a mechanism involving inhibition of IKKa and -b and subsequent NF-kB activation.Crossref, Medline, CAS, Google Scholar
- 27 Garcea G, Berry DP, Jones DJ et al.: Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol. Biomarkers Prev.14,120–125 (2005).Important paper showing that a daily dose of 3.6 g curcumin per day administered to colorectal cancer patients resulted in pharmacologically efficacious levels of curcumin in the colorectum, and reduced levels of the oxidative DNA adduct M(1)G in malignant colorectal tissue.Medline, CAS, Google Scholar
- 28 Huang MT, Wang ZY, Georgiadis CA, Laskin JD, Conney AH: Inhibitory effects of curcumin on tumor initiation by benzo[α]pyrene and 7,12-dimethylbenz[α]anthracene. Carcinogenesis13,2183–2186 (1992).Important study demonstrating that topical application of curcumin to skin inhibited carcinogen-induced DNA adduct formation and reduced tumor number.Crossref, Google Scholar
- 29 Hankinson O: The aryl hydrocarbon receptor complex. Annu. Rev. Pharmacol. Toxicol.35,307–340 (1995).Crossref, Medline, CAS, Google Scholar
- 30 Nebert DW, Roe AL, Dieter MZ et al.: Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem. Pharmacol.59,65–85 (2000).Crossref, Medline, CAS, Google Scholar
- 31 Deshpande SS, Maru GB: Effects of curcumin on the formation of benzo[α]pyrene derived DNA adducts in vitro. Cancer Lett.96,71–80 (1995).Crossref, Medline, CAS, Google Scholar
- 32 Rinaldi AL, Morse MA, Fields HW et al.: Curcumin activates the aryl hydrocarbon receptor yet significantly inhibits (-)-benzo[a]pyrene-7R-trans-7,8-dihydrodiol bioactivation in oral squamous cell carcinoma cells and oral mucosa. Cancer Res.62,5451–5456 (2002).Demonstrates that chemopreventive properties of curcumin are associated with modulation of carcinogen-activating enzymes through the aryl hydrocarbon receptor (AhR). Medline, CAS, Google Scholar
- 33 Singhal SS, Awasthi S, Pandya U et al.: The effect of curcumin on glutathione-linked enzymes in K562 human leukemia cells. Toxicol. Lett.109,87–95 (1999).Interesting study that relates curcumin chemoprevention to effects upon the AhR and CYP1A1.Crossref, Medline, CAS, Google Scholar
- 34 Stoner GD, Morse MA, Kelloff GJ: Perspectives in cancer chemoprevention. Environ. Health Perspect. 105 Suppl. 4,945–954 (1997).Crossref, Google Scholar
- 35 Ciolino HP, Daschner PJ, Wang TT, Yeh GC: Effect of curcumin on the aryl hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma cells. Biochem. Pharmacol.56, 197–206 (1998).Crossref, Medline, CAS, Google Scholar
- 36 Salh B, Assi K, Templeman V et al.: Curcumin attenuates DNB-induced murine colitis. Am. J. Physiol. Gastrointest. Liver Physiol.285, G235–G243 (2003).Demonstrates potent curcumin anti-inflammatory effects that achieves amelioration of colitis.Crossref, Medline, CAS, Google Scholar
- 37 Squires MS, Hudson EA, Howells L et al.: Relevance of mitogen activated protein kinase (MAPK) and phosphotidylinositol-3-kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells. Biochem. Pharmacol.65,361–376 (2003).Crossref, Medline, CAS, Google Scholar
- 38 Woo JH, Kim YH, Choi YJ et al.: 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. Carcinogenesis24,1199–1208 (2003).Crossref, Medline, CAS, Google Scholar
- 39 Liu JY, Lin SJ, Lin JK: Inhibitory effects of curcumin on protein kinase C activity induced by 12-O-tetradecanoyl-phorbol-13-acetate in NIH 3T3 cells. Carcinogenesis14, 857–861 (1993).Crossref, Medline, CAS, Google Scholar
- 40 Huang TS, Lee SC, Lin JK: Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells. Proc. Natl Acad. Sci. USA88,5292–5296 (1991).Crossref, Medline, CAS, Google Scholar
- 41 Nakamura K, Yasunaga Y, Segawa T et al.: Curcumin down-regulates AR gene expression and activation in prostate cancer cell lines. Int. J. Oncol.21,825–830 (2002).Medline, CAS, Google Scholar
- 42 Verma SP, Goldin BR, Lin PS: The inhibition of the estrogenic effects of pesticides and environmental chemicals by curcumin and isoflavonoids. Environ. Health Perspect.106,807–812 (1998).Crossref, Medline, CAS, Google Scholar
- 43 Kuo ML, Huang TS, Lin JK: Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. Biochim. Biophys. Acta1317,95–100 (1996).Crossref, Medline, CAS, Google Scholar
- 44 Jiang MC, Yang-Yen HF, Yen JJ, Lin JK: Curcumin induces apoptosis in immortalized NIH 3T3 and malignant cancer cell lines. Nutr. Cancer,26,111–120 (1996).Crossref, Medline, CAS, Google Scholar
- 45 Collett GP, Robson CN, Mathers JC, Campbell FC: Curcumin modifies Apc(min) apoptosis resistance and inhibits 2-amino 1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced tumour formation in Apc(min) mice. Carcinogenesis22,821–825 (2001). Demonstrates that inhibition of dietary mutagen associated tumor formation in a APCMin mouse model is associated with enhanced apoptosis.Crossref, Medline, CAS, Google Scholar
- 46 Samaha HS, Kelloff GJ, Steele V, Rao CV, Reddy BS: 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).Important study shows that chemopreventive properties of curcumin correlates with the degree of apoptosis. Medline, CAS, Google Scholar
- 47 Mahmoud NN, Carothers AM, Grunberger D et al.: Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis21,921–927 (2000).Shows that curcumin suppresses APC-associated intestinal carcinogenesis.Crossref, Medline, CAS, Google Scholar
- 48 Choudhuri T, Pal S, Agwarwal ML, Das T, Sa G: Curcumin induces apoptosis in human breast cancer cells through p53-dependent Bax induction. FEBS Lett.512,334–340 (2002).Crossref, Medline, CAS, Google Scholar
- 49 Jee SH, Shen SC, Tseng CR, Chiu HC, Kuo ML: Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells. J. Invest. Dermatol.111,656–661 (1998).Crossref, Medline, CAS, Google Scholar
- 50 Bush JA, Cheung KJ Jr, Li G: Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp. Cell Res.271,305–314 (2001).Crossref, Medline, CAS, Google Scholar
- 51 Collett GP, Campbell FC: Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. Carcinogenesis25,2183–2189 (2004).Demonstrates that c-jun N-terminal kinase, previously thought to be inhibited by curcumin, is activated by curcumin in human colon cancer cells and contributes to curcumin-induced apoptosis.Crossref, Medline, CAS, Google Scholar
- 52 Burgess AW: Growth control mechanisms in normal and transformed intestinal cells. Philos. Trans. R. Soc. Lond. B. Biol. Sci.353,903–909 (1998).Crossref, Medline, CAS, Google Scholar
- 53 Sancho E, Batlle E, Clevers H: Signaling pathways in intestinal development and cancer. Annu. Rev. Cell Dev. Biol.20,695–723 (2004).Crossref, Medline, CAS, Google Scholar
- 54 Gustavson MD, Crawford HC, Fingleton B, Matrisian LM: Tcf binding sequence and position determines β-catenin and Lef-1 responsiveness of MMP-7 promoters. Mol. Carcinog.41,125–139 (2004).Crossref, Medline, CAS, Google Scholar
- 55 Schafer B, Marg B, Gschwind A, Ullrich A: Distinct ADAM metalloproteinases regulate G protein-coupled receptor-induced cell proliferation and survival. J. Biol. Chem.279,47929–47938 (2004).Crossref, Medline, Google Scholar
- 56 Lange CA: Making sense of cross-talk between steroid hormone receptors and intracellular signaling pathways: who will have the last word? Mol.Endocrinol.18,269–278 (2004).CAS, Google Scholar
- 57 Maa MC, Leu TH, McCarley DJ, Schatzman RC, Parsons SJ: Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers. Proc. Natl Acad. Sci. USA92,6981–6985 (1995).Crossref, Medline, CAS, Google Scholar
- 58 Zhang Q, Thomas SM, Xi S et al.: SRC family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck cancer cells. Cancer Res.64,6166–6173 (2004).Crossref, Medline, CAS, Google Scholar
- 59 Kloth MT, Laughlin KK, Biscardi JS et al.: STAT5b, a mediator of synergism between c-Src and the epidermal growth factor receptor. J. Biol. Chem.278,1671–1679 (2003).Crossref, Medline, CAS, Google Scholar
- 60 Yao TP, Ku G, Zhou N, Scully R, Livingston DM: The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc. Natl Acad. Sci. USA93,10626–10631 (1996).Crossref, Medline, CAS, Google Scholar
- 61 Acevedo ML, Kraus WL: Mediator and p300/CBP-steroid receptor coactivator complexes have distinct roles, but function synergistically, during estrogen receptor alpha-dependent transcription with chromatin templates. Mol. Cell Biol.23,335–348 (2003).Crossref, Medline, CAS, Google Scholar
- 62 Ait-Si-Ali S, Polesskaya A, Filleur S et al.: CBP/p300 histone acetyl-transferase activity is important for the G1/S transition. Oncogene19,2430–2437 (2000).Crossref, Medline, CAS, Google Scholar
- 63 Jaiswal AS, Marlow BP, Gupta N, Narayan S: β-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene21, 8414–8427 (2002).Crossref, Medline, CAS, Google Scholar
- 64 Korutla L, Cheung JY, Mendelsohn J, Kumar R: Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin. Carcinogenesis16,1741–1715 (1995).Crossref, Medline, CAS, Google Scholar
- 65 Chen A, Xu J: Activation of PPARγ by curcumin inhibits Moser cell growth and mediates suppression of gene expression of cyclin D1 and EGFR. Am. J. Physiol. Gastrointest. Liver Physiol.288, G447–G456 (2005).Interesting report demonstrates that curcumin chemopreventive effects may be mediated through PPARg and suppression of cyclin D1 and EGFR. Crossref, Google Scholar
- 66 Leu TH, Su SL, Chuang YC, Maa MC: Direct inhibitory effect of curcumin on Src and focal adhesion kinase activity. Biochem. Pharmacol.66,2323–2331 (2003).Crossref, Medline, CAS, Google Scholar
- 67 Balasubramanyam K, Varier RA, Altaf M et al.: Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J. Biol. Chem.279,51163–51171 (2004).Demonstrates that curcumin can inhibit histone acetyltransferase (HAT) and HAT-dependent chromatin transcription.Crossref, Medline, CAS, Google Scholar
- 68 Takada Y, Bhardwaj A, Potdar P, Aggarwal BB: Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-κB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene,23,9247–9258 (2004).Important study demonstrates that ranks curcumin potency in a panel of nonsteroidal anti-inflammatory agents, for inhibition of COX-2 and cell proliferation.Crossref, Medline, CAS, Google Scholar
- 69 Chuang SE, Cheng AL, Lin JK, Kuo ML: Inhibition by curcumin of diethylnitrosamine-induced hepatic hyperplasia, inflammation, cellular gene products and cell-cycle-related proteins in rats. Food Chem. Toxicol.38,991–995 (2000).Crossref, Medline, CAS, Google Scholar
- 70 Chuang SE, Kuo ML, Hsu CH et al.: Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis,21,331–335 (2000).Crossref, Medline, CAS, Google Scholar
- 71 Blume-Jensen P, Hunter T: Oncogenic kinase signalling. Nature411,355–365 (2001).Crossref, Medline, CAS, Google Scholar
- 72 Dufour G, Demers MJ, Gagne D et al.: Human intestinal epithelial cell survival and anoikis. Differentiation state-distinct regulation and roles of protein kinase B/Akt isoforms. J. Biol. Chem.279,44113–44122 (2004).Crossref, Medline, CAS, Google Scholar
- 73 Kim S, Domon-Dell C, Wang Q et al.: PTEN and TNF-α regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-κB-dependent pathway. Gastroenterology123,1163–1178 (2002).Crossref, Medline, CAS, Google Scholar
- 74 Suh E, Traber PG: An intestine-specific homeobox gene regulates proliferation and differentiation. Mol. Cell Biol.16,619–625 (1996).Crossref, Medline, CAS, Google Scholar
- 75 Uesaka T, Kageyama N, Watanabe H: Identifying target genes regulated downstream of Cdx2 by microarray analysis. J. Mol. Biol.337,647–660 (2004).Crossref, Medline, CAS, Google Scholar
- 76 Sancho E, Batlle E, Clevers H: Live and let die in the intestinal epithelium. Curr. Opin. Cell Biol.15,763–770 (2003).Crossref, Medline, CAS, Google Scholar
- 77 Pap M, Cooper GM: Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J. Biol. Chem.273,19929–19932 (1998).Crossref, Medline, CAS, Google Scholar
- 78 Foltz DR, Santiago MC, Berechid BE, Nye JS: Glycogen synthase kinase-3β modulates notch signaling and stability. Curr. Biol.12,1006–1011 (2002).Crossref, Medline, CAS, Google Scholar
- 79 Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY: Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science294,2155–2158 (2001).Crossref, Medline, CAS, Google Scholar
- 80 Gout S, Marie C, Laine, M et al.: Early enterocytic differentiation of HT-29 cells: biochemical changes and strength increases of adherens junctions. Exp. Cell Res.299,498–510 (2004). Crossref, Medline, CAS, Google Scholar
- 81 Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA: Peroxisome proliferator-activated receptor (PPAR)γ: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology135, 798–800 (1994).Google Scholar
- 82 Kato M, Kusumi T, Tsuchida S, Tanaka M, Sasaki M, Kudo H: Induction of differentiation and peroxisome proliferator-activated receptor gamma expression in colon cancer cell lines by troglitazone. J. Cancer Res. Clin. Oncol.130,73–79 (2004).Crossref, Medline, CAS, Google Scholar
- 83 Critchley DR: Focal adhesions – the cytoskeletal connection. Curr. Opin. Cell Biol.12,133–139 (2000).Crossref, Medline, CAS, Google Scholar
- 84 Burridge K, Wennerberg K: Rho and Rac take center stage. Cell116,167–179 (2004).Comprehensive review on the regulation of Rho and Rac GTPases and their effects on the actin cytoskeleton.Crossref, Medline, CAS, Google Scholar
- 85 Hall A: Rho GTPases and the actin cytoskeleton. Science279,509–514 (1998).Interesting insight into how Rho proteins control transcription and cellular adhesion as well as regulate the actin cytoskeleton.Crossref, Medline, CAS, Google Scholar
- 86 Raftopoulou M, Hall A: Cell migration: Rho GTPases lead the way. Dev. Biol.265,23–32 (2004).Interesting review of Rho GTPases in cell migration.Crossref, Medline, CAS, Google Scholar
- 87 Westhoff MA, Serrels B, Fincham VJ, Frame, MC, Carragher NO: SRC-mediated phosphorylation of focal adhesion kinase couples actin and adhesion dynamics to survival signaling. Mol. Cell Biol.24,8113–8133 (2004).Crossref, Medline, CAS, Google Scholar
- 88 Fingleton BM, Heppner Goss KJ, Crawford HC, Matrisian LM: Matrilysin in early stage intestinal tumorigenesis. APMIS107,102–110 (1999).Concise review of the regulation of expression of the matrix metalloproteinase matrilysin and its role in the early stages of intestinal tumorigenesis.Crossref, Medline, CAS, Google Scholar
- 89 Swarnakar S, Ganguly K, Kundu P, Banerjee A, Maity P, Sharma AV: Curcumin regulates expression and activity of matrix metalloproteinases-9 and -2 during prevention and healing of indomethacin-induced gastric ulcer. J. Biol. Chem. (2004).Interesting study which demonstrates that curcumin can directly inhibit MMP-9.Medline, Google Scholar
- 90 Banerji A, Chakrabarti J, Mitra A, Chatterjee A: Effect of curcumin on gelatinase A (MMP-2) activity in B16F10 melanoma cells. Cancer Lett.211,235–242 (2004).Crossref, Medline, CAS, Google Scholar
- 91 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.21,2895–2900 (2001). Medline, CAS, Google Scholar
- 92 Kuttan R, Sudheeran PC, Joseph CD: Turmeric and curcumin as topical agents in cancer therapy. Tumori.73,29–31 (1987).Crossref, Medline, CAS, Google Scholar
- 93 Garcea G, Jones DJ, Singh R et al.: Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br. J. Cancer90,1011–1015 (2004).Crossref, Medline, CAS, Google Scholar

