Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer cells.

PURPOSE: Multiple studies have indicated that cyclooxygenase-2 (COX-2) inhibitors may prevent colon cancer, which is one of the leading causes of cancer death in the western world. Recent studies, however, showed that their long-term use may be limited due to cardiovascular toxicity. This study aims to investigate whether curcumin potentiates the growth inhibitory effect of celecoxib, a specific COX-2 inhibitor, in human colon cancer cells. EXPERIMENTAL DESIGN: HT-29 and IEC-18-K-ras (expressing high levels of COX-2), Caco-2 (expressing low level of COX-2), and SW-480 (no expression of COX-2) cell lines were exposed to different concentrations of celecoxib (0-50 micromol/L), curcumin (0-20 micromol/L), and their combination. COX-2 activity was assessed by measuring prostaglandin E(2) production by enzyme-linked immunoassay. COX-2 mRNA levels were assessed by reverse transcription-PCR. RESULTS: Exposure to curcumin (10-15 micromol/L) and physiologic doses of celecoxib (5 micromol/L) resulted in a synergistic inhibitory effect on cell growth. Growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Curcumin augmented celecoxib inhibition of prostaglandin E(2) synthesis. The drugs synergistically down-regulated COX-2 mRNA expression. Western blot analysis showed that the level of COX-1 was not altered by treatment with celecoxib, curcumin, or their combination. CONCLUSIONS: Curcumin potentiates the growth inhibitory effect of celecoxib by shifting the dose-response curve to the left. The synergistic growth inhibitory effect was mediated through a mechanism that probably involves inhibition of the COX-2 pathway and may involve other non-COX-2 pathways. This synergistic effect is clinically important because it can be achieved in the serum of patients receiving standard anti-inflammatory or antineoplastic dosages of celecoxib.

Celecoxib but not rofecoxib inhibits the growth of transformed cells in vitro.

PURPOSE: Nonsteroidal anti-inflammatory drugs reduce the risk of colorectal cancer. The cyclooxygenase (COX) pathway of arachidonic acid metabolism is an important target for nonsteroidal anti-inflammatory drugs. Increased expression of COX-2 was recently shown to be an important step in the multistep process of colorectal cancer carcinogenesis. The new COX-2-specific inhibitors offer the benefit of cancer protection without the gastrointestinal toxicity reported for the old drugs. The purpose of this study was to compare the growth effects of two specific COX-2 inhibitors, celecoxib (Pfizer, Inc., New York, NY), and rofecoxib (Merck, White House Station, NJ) in normal and transformed enterocytes. EXPERIMENTAL DESIGN: Cultures of normal rat intestinal epithelial cell line, IEC-18, vector control cells, c-K-ras, c-K-ras-bak, and antisense-bak derivatives were treated with different dosages of celecoxib (0-60 micro M) and rofecoxib (0-20 micro M). Cell cycle analysis and apoptosis were assessed by fluorescence-activated cell sorting analysis. Protein expression was assessed by Western blot analysis and caspases 3 and 8 activities by ELISA. RESULTS: Celecoxib inhibited cell growth and induced apoptosis in a time- and dose-dependent manner. IEC18 parental cells were two to four times more resistant to celecoxib than ras, ras-bak, and antisense bak transformed cells that overexpress the COX-2 protein. The induction of apoptosis by celecoxib involved the caspase pathways. Rofecoxib, up to its maximal concentration of 20 micro M, did not inhibit cell growth or induce apoptosis. CONCLUSIONS: Celecoxib may prove to be a very efficient component in the prevention and treatment of gastrointestinal tumors because it inhibits the growth of cancerous cells without affecting the growth of normal cells.

The I1307K adenomatous polyposis coli gene variant does not contribute in the assessment of the risk for colorectal cancer in Ashkenazi Jews.

Ashkenazi Jews with the I1307K adenomatous polyposis coli gene variant were suggested to confer a higher risk for colorectal cancer (CRC). We assessed the clinical importance of this polymorphism in Israeli Jews at average and elevated risk for CRC. Among 1,370 consecutive subjects that were examined, 975 Ashkenazi Jews were stratified into those at average risk (no personal or family history of colorectal neoplasia) and those at high risk. DNA was obtained from peripheral leukocytes and amplified by PCR, with primers designed to detect the I1307K variant. Overall, I1307K polymorphism was found in 7.1% (9.1% among Ashkenazi and 1.7% among non-Ashkenazi Jews). The carrier rate was 8.3 and 9.3% in average and high-risk Ashkenazim, respectively (P = 0.65). The overall odds ratio for neoplasia in carriers was 1.43 (95% confidence interval, 0.89-2.30). Age, gender, and the histopathological features of adenomas and cancers did not differ between carriers and noncarriers. No interaction on the CRC risk was found between I1307K variant and lifestyle modifiers (such as cigarette smoking, alcohol consumption, high body mass index, low physical activity, and vitamins/antioxidant intake). The I1307K adenomatous polyposis coli gene variant is not an important marker for increased risk for CRC. It confirms previous reports of a slight nonsignificant increase (OR, 1.4) in the risk of CRC in these carriers. There is no interaction effect on the risk of colorectal neoplasia between the I1307K variant and various lifestyle risk factors. The usual recommended screening and surveillance strategies should be used for carriers of this polymorphism.

Down-regulation of prostaglandin E2 by curcumin is correlated with inhibition of cell growth and induction of apoptosis in human colon carcinoma cell lines.

Several in vitro and in vivo studies have demonstrated an association between curcumin, a diferuloylmethane derived from the plant Curcuma longa, and colorectal cancer (CRC) prevention. Nevertheless, the molecular mechanism responsible for the chemopreventive effect of curcumin is not well understood and most probably involves several pathways. Several studies indicate that curcumin may exert its effect by specifically inhibiting the cyclooxygenase-2 (COX-2) isoenzyme, which is up-regulated in 40 to 50% of colorectal polyps and in up to 85% of CRCs. However, other studies have suggested that curcumin may also inhibit polyps formation by COX-2 independent mechanisms (eg, inhibition of ErbB-1, AkT). The aim of this study was to evaluate whether curcumin's effect on the inhibition of cell growth and induction of apoptosis in human colon carcinoma cell lines is correlated with inhibition of PGE2 synthesis and down-regulation of COX-2. HT29 cells (expressing COX-2) and SW480 (deficient of COX-2) were exposed to different concentrations (0-50 microM) of curcumin for 72 hours. Growth inhibition was assessed by Coulter counter. Cell viability was assessed by the ability of metabolically active cells to reduce tetrazolium salt to colored formazan compounds (tetrazolium salt assay). Apoptosis was measured by two independent methods: flow cyto-metric analysis and 4'-6-Diamidino-2-phenylindole (DAPI) staining. Activity of COX-2 was evaluated by measuring prostaglandin E2 (PGE2) concentration using a specific enzyme-linked immunoassay. COX-1 and COX-2 expressions were measured by Western blot analysis. There was a significant difference between curcumin effect on COX-2-expressing (HT29: inhibitory concentration 50% [IC50] = 15 microM) and COX-2-deficient (SW480: IC50 = 40 microM) cells. Similarly, induction of apoptosis was higher in cells expressing COX-2. Western blot analysis and PGE2 immunoassay showed that curcumin inhibited COX-2 protein activity and expression in a dose-dependent manner. In conclusion, inhibition of cell survival and induction of apoptosis by curcumin in colorectal adenocarcinoma cell lines is associated with the inhibition of PGE2 synthesis and down-regulation of COX-2.