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

Abstract

Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modi®cation might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during in¯ammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-in¯amma-tory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor a or fecapentaene-12. Induction of COX2 by in¯ammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kB). Since curcumin inhibits NF-kB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kBsequestering protein, IkB. Recently components of this pathway, NF-kB-inducing kinase and IkB kinases, IKKa and b, which phosphorylate IkB to release NF-kB, have been characterised. Curcumin prevents phosphorylation of IkB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health e ects, makes curcumin an important candidate for consideration in colon cancer prevention.

Preclinical assessment of curcumin as a potential therapy for B‐CLL

“…Subsequent studies confirmed curcumininduced inhibition of NF-kB translocation in multiple cell types, including colon [3], gastric [4], pancreatic [5], and squamous epithelial tumor cell lines [6] as well as B-cell lymphoma and multiple myeloma cell lines [7,8]. Although the precise mechanism by which NF-kB translocation is inhibited remains unclear, Plummer et al demonstrated that curcumin reduced NF-kB translocation in HEK293 cells transfected with NIK, IKKa, or IKKb kinases [3]. These authors suggested that curcumin-induced effects on NF-kB translocation could be due to a direct effect on the activity of one of these kinases.…”

“…In studies of the myeloid cell line ML-1a, Singh and Aggarwal reported that curcumin inhibited IkBa phosphorylation, degradation, and NF-kB translocation induced by a diverse range of stimuli including TNF, hydrogen peroxide, and phorbol esters [2]. Subsequent studies confirmed curcumininduced inhibition of NF-kB translocation in multiple cell types, including colon [3], gastric [4], pancreatic [5], and squamous epithelial tumor cell lines [6] as well as B-cell lymphoma and multiple myeloma cell lines [7,8]. Although the precise mechanism by which NF-kB translocation is inhibited remains unclear, Plummer et al demonstrated that curcumin reduced NF-kB translocation in HEK293 cells transfected with NIK, IKKa, or IKKb kinases [3].…”

Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration

“…In Apc Min þ mice, a model of familial adenomatous polyposis, dietary curcumin reduced adenoma burden (Perkins et al, 2002b), which was accompanied by a reduction in adenoma levels of the oxidative DNA adduct (2-deoxy-b-dierythropentafuranosyl)pyrimido[1,2-a]-purin-10(3H)-one (malondialdehyde-DNA adduct, M 1 G) (Perkins et al, 2002a). Other mechanisms by which curcumin may exert chemopreventive action are interference with the transcription of the enzyme cyclooxygenase-2 (COX-2) (Plummer et al, 1999), induction of apoptosis (Kuo et al, 1996;Kawamori et al, 1999) and antiangiogenesis (Arbiser et al, 1998). The concentrations of curcumin needed to exert these effects in cells in vitro, range from 5 to 50 mM (Sharma, 1976;Kunchandy and Rao, 1990;Huang et al, 1991;Tonessan and Greenhill, 1992;Reddy and Lokesh, 1992;Subramanian et al, 1994;Plummer et al, 1999).…”

“…Other mechanisms by which curcumin may exert chemopreventive action are interference with the transcription of the enzyme cyclooxygenase-2 (COX-2) (Plummer et al, 1999), induction of apoptosis (Kuo et al, 1996;Kawamori et al, 1999) and antiangiogenesis (Arbiser et al, 1998). The concentrations of curcumin needed to exert these effects in cells in vitro, range from 5 to 50 mM (Sharma, 1976;Kunchandy and Rao, 1990;Huang et al, 1991;Tonessan and Greenhill, 1992;Reddy and Lokesh, 1992;Subramanian et al, 1994;Plummer et al, 1999). Little is known about the potential pharmacological efficacy of products of the metabolic conjugation and reduction of curcumin.…”

Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

“…Overexpression of COX-2 caused by hypoxia in human umbilical vein endothelial cells and in human alveolar epithelial cells, and by interleukin-1 (IL-1) in rheumatoid synoviocytes has been shown to be mediated by the nuclear factor-kB (NF-kB). Recently, inhibition of this latter pathway in vitro by curcumin (an inhibitor of NF-kB activation) has been shown to attenuate COX-2 expression in colon cells (Plummer et al, 1999), indicating that NF-kB may play an important role in COX-2 induction. Should this be the case in neoplastic cells, then the NF-kB control of COX-2 expression would be important in the development and progression of human colorectal carcinoma.…”