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Biomedical subjects

Nadir Arber

Publications and source records attributed to Nadir Arber.

At least 19 recordsLinked to original sources
PubMed2007

Suppression of gastric cancer cell growth by targeting the beta-catenin/T-cell factor pathway.

BACKGROUND: Functional activation of beta-catenin/T-cell factor (Tcf) signaling plays an important role in the early events of carcinogenesis. Recently, it was demonstrated that adenomatous polyposis coli or beta-catenin genes are mutated frequently in gastric cancer cells. The objective of the current study was to use a gene-targeting approach to kill human gastric cancer cells selectively with activated beta-catenin/Tcf signaling. METHODS: A recombinant adenovirus that carries a lethal gene (p53 up-regulated modulator of apoptosis [PUMA]) under the control of a beta-catenin/Tcf-responsive promoter (AdTOP-PUMA) was used selectively to target gastric cancer cells (AGS) that posses an active beta-catenin/Tcf pathway. The combined effect of AdTOP-PUMA and several chemotherapeutic agents (5-florouracil, doxorubicin, paclitaxel) also was evaluated. Cell viability was measured by methylene blue assay, protein expression was measured by Western blot analysis, and cell cycle and apoptosis were evaluated by fluorescent-activated cell sorter analysis. RESULTS.: The TOP-PUMA adenovirus inhibited AGS cell growth in a dose- and time-dependent fashion. Growth inhibition was associated with the up-regulation of PUMA expression and the induction of apoptosis. Chemotherapy synergistically enhanced the killing effect of AdTOP-PUMA. CONCLUSIONS: Selective targeting of gastric cancer cells with the activated beta-catenin pathway may be a novel and effective therapy in gastric cancer. Combination of this gene-therapy approach with standard therapy may improve efficacy and reduce toxicity.

Adenoviridae↗
PubMed2007

Celecoxib and curcumin additively inhibit the growth of colorectal cancer in a rat model.

BACKGROUND: Multiple studies have indicated that specific COX-2 inhibitors may prevent CRC. However, the long-term use of COX-2 inhibitors is not toxicity-free and may be limited due to its cardiovascular side effects. The present study was carried out to examine the chemopreventive effects of celecoxib and curcumin alone and in combination using the 1,2-dimethylhydrazine (DMH) rat model. METHODS: Male rats were injected with DMH and randomly divided into four groups that consumed one of the following diets: (a) AIN-076 control diet; (b) AIN-076/curcumin (0.6%); (c) AIN-076/celecoxib (0.16%), or (d) AIN-076/celecoxib (0.16%) and curcumin (0.6%). Aberrant crypt foci (ACF) were identified by intensive staining with methylene blue in comparison to the surrounding normal crypts. RESULTS: The average number of ACF per rat colon was 64.2 +/- 3 in the control group, 39 +/- 5 and 47 +/- 10 for the curcumin- and celecoxib-treated group, respectively, and 24.5 +/- 6 in the group that had received both agents. CONCLUSIONS: In vivo, curcumin augments the growth inhibitory effect of celecoxib. This may be clinically important as this dose of celecoxib can be achieved in human serum following standard anti-inflammatory dosing of 100 mg.

Analysis of Variance↗
PubMed2006

Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas.

BACKGROUND: Cyclooxygenase-2 (COX-2) inhibitors have been shown to reduce colorectal adenomas but have been associated with increased cardiovascular risk. METHODS AND RESULTS: The Adenoma Prevention With Celecoxib (APC) trial studied celecoxib 200 mg twice daily and 400 mg twice daily and the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial used 400 mg once daily totest the efficacy and safety of celecoxib against placebo in reducing colorectal adenoma recurrence after polypectomy. An independent safety committee for both studies adjudicated and categorized serious cardiovascular events and then combined individual patient data from these long-term trials to improve the estimate of the cardiovascular risk and blood pressure changes associated with celecoxib compared with placebo. For adjudicated cardiovascular events, 77% and 54% in APC and PreSAP, respectively, had 37 months of follow-up. For APC and PreSAP combined, 83 patients experienced cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure. The hazard ratio for this prespecified composite end point was 2.6 (95% confidence interval [CI], 1.1 to 6.1) in patients taking 200 mg twice daily, 3.4 (95% CI, 1.5 to 7.9) in patients taking 400 mg twice daily in APC, and 1.3 (95% CI, 0.6 to 2.6) in patients taking 400 mg once daily in PreSAP (P for heterogeneity = 0.13 comparing the combined doses in APC with the dose in PreSAP). The overall hazard ratio for this composite end point was 1.9 (95% CI, 1.1 to 3.1). Both dose groups in APC showed significant systolic blood pressure elevations at 1 and 3 years (200 mg twice daily: 1 year, 2.0 mm Hg; 3 years,2.6 mm Hg; 400 mg twice daily: 1 year, 2.9 mm Hg; 3 years, 5.2 mm Hg); however, the 400 mg once daily group inPreSAP did not (P0.0001 between studies). CONCLUSIONS: Celecoxib at 200 or 400 mg twice daily or 400 mg once daily showed a nearly 2-fold-increased cardiovascular risk. The trend for a dose-related increase in cardiovascular events and blood pressure raises the possibility that lower doses or other dose intervals may be associated with less cardiovascular risk.

Adenoma↗
PubMed2006

Celecoxib for the prevention of colorectal adenomatous polyps.

BACKGROUND: Overexpression of cyclooxygenase 2 (COX-2) has been associated with colorectal adenomatous polyps and cancer, prompting researchers to propose its inhibition as a chemopreventive intervention. METHODS: The Prevention of Colorectal Sporadic Adenomatous Polyps trial was a randomized, placebo-controlled, double-blind study of the COX-2 inhibitor celecoxib given daily in a single 400-mg dose. At 107 centers in 32 countries, we randomly assigned 1561 subjects who had had adenomas removed before enrollment to receive celecoxib (933 subjects) or placebo (628 subjects) daily, after stratification according to the use or nonuse of low-dose aspirin. The primary outcome was detection of adenomas at either year 1 or year 3 by colonoscopy and was compared among the groups with the use of the Mantel-Cox test. RESULTS: Colonoscopies were performed at year 1 on 88.7 percent of the subjects who had undergone randomization and at year 3 on 79.2 percent. Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both. The cumulative rate of adenomas detected through year 3 was 33.6 percent in the celecoxib group and 49.3 percent in the placebo group (relative risk, 0.64; 95 percent confidence interval, 0.56 to 0.75; P<0.001). The cumulative rate of advanced adenomas detected through year 3 was 5.3 percent in the celecoxib group and 10.4 percent in the placebo group (relative risk, 0.49; 95 percent confidence interval, 0.33 to 0.73; P<0.001). Adjudicated serious cardiovascular events occurred in 2.5 percent of subjects in the celecoxib group and 1.9 percent of those in the placebo group (relative risk, 1.30; 95 percent confidence interval, 0.65 to 2.62). CONCLUSIONS: The use of 400 mg of celecoxib once daily significantly reduced the occurrence of colorectal adenomas within three years after polypectomy. (ClinicalTrials.gov number, NCT00141193 [ClinicalTrials.gov].).

Adenoma↗
PubMed2006

Correlated expression of high-sensitivity C-reactive protein in relation to disease activity in inflammatory bowel disease: lack of differences between Crohn's disease and ulcerative colitis.

BACKGROUND/AIMS: As opposed to regular C-reactive protein (CRP) assays, the introduction of high-sensitivity ones has enabled us to detect low grade inflammation in patients with inflammatory bowel disease (IBD). We addressed the subject of the degree of correlation between the concentration of high-sensitivity CRP (hs-CRP) and the inflammatory IBD activity score. METHODS: Included were 90 patients with Crohn's disease (CD), 70 with ulcerative colitis (UC) and 160 controls. Disease activity was determined using CD activity index (CDAI) for CD and Mayo score for UC. The Dade Boering BNII Nephelometer was used to determine the hs-CRP concentrations. RESULTS: The coefficient of correlation between hs-CRP and the disease activity score was similar for both UC (0.26) and CD (0.36). CONCLUSIONS: These findings are relevant for therapeutic intervention in which a greater absolute reduction in the hs-CRP concentration in CD patients (who generally present higher CRP concentrations than those found in UC) might be interpreted as a better response compared to the same absolute reduction in UC patients. This information is needed for clinicians using the hs-CRP assay to estimate IBD disease activity in daily practice.

Adult↗
PubMed2006

Celecoxib leads to G2/M arrest by induction of p21 and down-regulation of cyclin B1 expression in a p53-independent manner.

A unique in vitro system has been developed in our lab that consists of normal enterocytes derived from the rat ileum (IEC-18 cells) and their transformed derivatives with c-K-ras (R1 cells), anti-sense bak (B3 cells) and cyclin D1 (D1 cells). R1 and B3 cells express high level of COX-2 protein and PGE2. IEC 18 and D1 cells express negligible amount of COX-2, and produce very low level of PGE2. A relatively low dose of celecoxib (5-10 microM) induced G2/M arrest, followed by induction of apoptosis in the transformed but not in the normal cells. Down-regulation of cyclin B1 and up-regulation of p21 expressions independent of p53 might have cause this cell cycle block. Growth inhibition was related to COX-2 function with 90-95% reduction in PGE2 production. These findings may be of clinical importance, since low concentration of celecoxib can be achieved in human serum following standard anti-inflammatory (100-200 mg bid) regime.

Animals↗
PubMed2006

MF tricyclic and sulindac retard tumor formation in an animal model.

New selective cyclooxygenase-2 inhibitors offer the benefit of cancer protection with less gastrointestinal toxicity associated with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). We hypothesize that MF tricyclic and sulindac can retard all stages of tumor formation in nude mice. In a blinded placebo controlled study, 3 types of experiments were performed: 1) 2.5 x 10(6) cells were injected into 2 flanks of nude mice subcutaneously, as a model for in situ cancer (n = 192); 2) 1 x 10(6) cells were injected into the cecum of mice as a model for in situ colorectal cancer (n = 78) and 3) 0.5 x 10(6) cells were implanted into the splenic subcapsule to establish a colorectal cancer liver metastasis model (n = 78). The animals were fed with standard chow containing either placebo, MF tricyclic (67 mg/kg of chow) or sulindac (150 mg/kg of chow). Mice that were given MF tricyclic or sulindac, at clinical anti-inflammatory plasma concentrations, were significantly more tumor free and had significantly smaller primary tumors and fewer metastases, as compared to mice that consumed placebo. The mortality and the latency period were significantly better in the treatment groups. These findings suggest that selective COX-2 inhibitors may serve as an adjunct to standard therapy in colorectal cancer.

Administration, Oral↗
PubMed2006

The aer-o-scope: proof of concept of a pneumatic, skill-independent, self-propelling, self-navigating colonoscope.

BACKGROUND & AIMS: Endoscopic screening of the colon with available instruments requires considerable training, is often painful, and carries a risk of perforation. New instrument platforms for endoscopic screening could be useful. The aim of this study was to evaluate the extent of colonic intubation by using a novel self-propelled, self-navigating endoscope (the Aer-O-Scope; GI View Ltd, Ramat Gan, Israel). METHODS: Twelve young healthy volunteers underwent complete bowel preparation followed by a nonsedated examination using the novel device. Each examination was followed by a standard colonoscopy for safety evaluation. Cecal intubation was confirmed by endoscopic landmarks and fluoroscopy. RESULTS: In 10 out of 12 subjects (83%) the cecum was successfully reached, whereas in 2 cases the Aer-O-Scope advanced to the hepatic flexure. The time to complete advancement to cecum averaged 14.0 +/- 7 minutes, and the driving pressures averaged 34 +/- 2.3 milibar. Two subjects requested analgesics during the procedures (in both cases the cecum was reached). Four subjects experienced sweating and a bloating sensation that resolved spontaneously. All subjects were followed up to 48 hours and then for 30 days postprocedure, and no complications were observed. CONCLUSIONS: In a preliminary pilot feasibility study of this new instrument, the Aer-O-Scope effectively intubated all or most of the colon. Further clinical studies are warranted.

Adult↗
PubMed2006

CD24 is a new oncogene, early at the multistep process of colorectal cancer carcinogenesis.

BACKGROUND & AIMS: The aim of this study was to identify genes that play a role in colorectal cancer (CRC) carcinogenesis by analysis of differential gene expression of normal and transformed CRC cell lines. METHODS: Gene expression array analysis ([RG-U34] GeneChip) was performed in normal and transformed rat intestinal epithelial cells before and after exposures to celecoxib. In particular, we were looking for (1) altered gene expression in the transformed cells that reverts to normal following exposure to a selective cyclooxygenase-2 inhibitor, (2) novel genes, and (3) genes encoding membrane receptors or ligands. As a validation of the results and for human patients, immunohistochemistry was performed on 398 biological samples from the gastrointestinal tract (normal, polyps, and adenocarcinomas). Human cancer cell lines were tested for their response to anti-CD24 monoclonal antibodies. RESULTS: A total of 1081 genes were differently expressed following malignant transformation; 71 genes showed altered expression that reverted to normal following treatment with celecoxib, including the CD24 gene. Immunohistochemistry confirmed that increased expression of CD24 is an early event in CRC carcinogenesis. It was expressed in 90.7% of adenomas and 86.3% of CRCs. Very low expression was seen in normal epithelium (16.6%). Human cancer cell lines showed growth inhibition in response to the antibodies, according to their expression levels of CD24 and in dose- and time-dependent manners. These results were repetitive for 3 different antibodies. CONCLUSIONS: CD24 is overexpressed in the colonic mucosa, already at an early stage of carcinogenesis. It may be a useful target for early detection and in CRC therapy.

Adenocarcinoma↗
PubMed2006

Coxibs and cancer prevention.

Preventive medicine is becoming a cornerstone in our concept of health. This is especially significant in regard to cancer, as cancer is predicted to become the leading cause of death, surpassing heart disease, by the end of this decade. The prevention of colorectal cancer (CRC) has become an important public health goal because of the high incidence of CRC, with more than 945,000 new cases expected worldwide in 2006, and the considerable mortality and morbidity associated, with more than 492,000 deaths expected worldwide in the same year. The past 2 decades have seen the emergence of chemopreventive agents that have 1 of 3 effects: inhibiting, delaying, or reversing carcinogenesis. Notwithstanding a substantial body of evidence suggesting an inverse relationship between aspirin or nonsteroidal anti-inflammatory drug use and CRC incidence and mortality, the use of traditional nonsteroidal anti-inflammatory drugs in the chemoprevention of CRC is limited by their gastrointestinal toxicity. The favorable gastrointestinal safety profile of selective cyclooxygenase-2 inhibitors has therefore made them particularly attractive for this purpose. There has been concern, however, that selective cyclooxygenase-2 inhibitors may increase the risk of cardiovascular events, possibly by reducing endothelial prostacyclin production while leaving platelet thromboxane A2 generation unopposed. In the intriguing jigsaw puzzle of cancer prevention, we now have a definite positive answer for the basic question "if," but several other parts of the equation (proper patient selection, ultimate drug, optimal dosage, and duration) are missing. The most challenging task is to find the proper place for these interventions in the entire effort of cancer prevention, in subjects at risk for colorectal neoplasia, and in those at risk for other tumors. The achievement of this important goal may contribute to the conversion of CRC into a truly preventable disease.

Animals↗
PubMed2006

The prevalence rate and anatomic location of colorectal adenoma and cancer detected by colonoscopy in average-risk individuals aged 40-80 years.

BACKGROUND: The role of screening colonoscopy for colorectal (CR) neoplasia in average-risk population, remains to be determined. OBJECTIVES: To evaluate the prevalence and anatomic location of CR adenoma and carcinoma and the morbidity of colonoscopy in individuals at average risk for CR cancer (CRC). METHODS: A retrospective prevalence study of subjects aged 40-80 yr, with no cancer-related symptoms, personal or family history of CR neoplasia, who underwent a colonoscopy. RESULTS: Enrolled were 1,177 persons; 183 aged 40-49 yr (young), 917 aged 50-75 yr, and 77 aged 76-80 yr (elderly). The prevalence of overall CR neoplasia, advanced neoplasia, and cancer was 20.9%, 6.3%, and 1.1%, respectively. In the 50-75 age group, the prevalence of overall adenoma, advanced neoplasia, and cancer was 21.3%, 6.7%, and 1.2%, respectively. Of the 206 neoplasia cases, 21-43% harbored proximal neoplasia beyond the reach of sigmoidoscopy, without distal lesions. Among the elderly, the prevalence of overall adenoma, advanced neoplasia, and cancer reached 26.0%, 14.3%, and 2.6%, respectively. In the young group, 9.8% had overall neoplasia, 1.1% had advanced adenoma, and none had CRC. Procedure-related morbidity rate was 0.1%, with no perforations, bleedings, or mortality. CONCLUSIONS: Screening colonoscopy in average-risk subjects demonstrated a considerable prevalence of CR neoplasia and proximal lesions beyond the reach of sigmoidoscopy. The morbidity rate was negligible. Primary screening colonoscopy should be considered in health programs for the average-risk population, beginning at the age of 50 yr. The significantly high rate of advanced and proximal neoplasia in the elderly, encourages the inclusion of healthy subjects aged 76-80 yr in future prospective studies.

Adenocarcinoma↗
PubMed2006

Targeting the active beta-catenin pathway to treat cancer cells.

The adenomatous polyposis coli or beta-catenin genes are frequently mutated in colorectal cancer cells, resulting in oncogenic activation of beta-catenin signaling. We tried to establish in vitro and in vivo models for selectively killing human cancer cells with an activated beta-catenin/T-cell factor (Tcf) pathway. We used a recombinant adenovirus that carries a lethal gene [p53-up-regulated modulator of apoptosis (PUMA)] under the control of a beta-catenin/Tcf-responsive promoter (AdTOP-PUMA) to selectively target human colorectal cancer cells (SW480, HCT116, DLD-1, and LS174T), hepatocellular carcinoma (HepG2), and gastric cancer cells (AGS) in which the beta-catenin/Tcf pathway is activated, and compared its efficiency in killing cancer cells in which this pathway is inactive or only weakly active. AdFOP-PUMA, carrying a mutant Tcf-binding site, was used as control virus. The combined effect of AdTOP-PUMA with several chemotherapeutic agents (5-florouracil, doxorubicin, and paclitaxel) was also evaluated. The effect of AdTOP-PUMA on colorectal cancer cells was also examined in nude mice: SW480 cells were infected with the AdTOP-PUMA and AdFOP-PUMA, and then inoculated s.c. into nude mice. The TOP-PUMA adenovirus inhibited cell growth in a dose-dependent fashion, depending on the signaling activity of beta-catenin. The growth of cells displaying high levels of active beta-catenin/Tcf signaling was inhibited after infection with AdTOP-PUMA, whereas that of cells with low levels of beta-catenin signaling was not. Growth inhibition was associated with induction of apoptosis. Chemotherapy synergistically enhanced the effect of AdTOP-PUMA. A combination of the adenovirus system with standard therapy may improve the efficacy and reduce the toxicity of therapy in humans.

Adenoviridae↗
PubMed2006

Chemoprevention of colorectal cancer: two steps forward, one step back?

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in the Western world. The poor survival rate has prompted the emphasis on prevention of this disease. Removal of adenomas at colonoscopy is highly effective and is the cornerstone of screening/surveillance strategies. However, screening efforts have had limited impact owing to low compliance with guidelines. Chemoprevention aims to prevent the development or recurrence of precancerous lesions and cancers with the use of compounds that block the carcinogenic process. A major advantage was the establishment and understanding of the multistage process of CRC carcinogenesis. Progress has been remarkable because of the availability of reliable animal models and clinical studies using colonic adenomas as a reliable and economic target for testing chemopreventive agents. Nonsteroidal anti-inflammatory drugs have drawn the most attention. Sulindac and celecoxib were shown to be effective in promoting polyp regression in high-risk individuals with familial adenomatous polyposis. In the more common sporadic setting, the Adenomatous Polyp PRevention On Vioxx (rofecoxib), Adenoma Prevention with Celecoxib and Prevention of Sporadic Adenomatous Polyps (celecoxib) trials have demonstrated a significant reduction in adenoma recurrence, but important concerns were raised regarding cardiovascular toxicity associated with selective cyclo-oxygenase-2 inhibitors. These landmark studies are very important, as they are a proof-of-concept that we can prevent CRC. More clinical studies are required to better select high-risk patients with safer regimens. Potential advantage versus risk for a given chemopreventive agent will have to be assessed on an individual basis. Currently, the only approved agent for chemoprevention is celecoxib in high-risk individuals with familial adenomatous polyposis.

Adenoma↗
PubMed2006

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.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Cyclooxygenase-2 inhibition prevents colorectal cancer: from the bench to the bed side.

Cancer is predicted to become the leading cause of death--surpassing heart disease--by the end of this decade. Colorectal cancer is a major health concern, with more than 1,000,000 new cases and 500,000 deaths expected worldwide per year. There is much evidence to suggest a link between the consumption of non-steroidal anti-inflammatory drugs (NSAIDs) and the prevention of colorectal cancer (CRC). The consumption of NSAIDs is not problem free, and the number of deaths due to NSAIDs equals the number of deaths from AIDS or leukemia. Therefore, although chemoprevention of CRC is possible, drugs that have more acceptable side effect profiles than the currently available NSAIDs are required. Since up to 50% of polyps and 85% of colonic tumors in humans overexpress cyclooxygenase (COX-2), COX-2 inhibitors are an ideal drug candidate for CRC prevention or treatment.

Animals↗
PubMed2005

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.

Analysis of Variance↗
PubMed2005

Chemoprevention of colorectal cancer: ready for routine use?

In the third millennium, preventive medicine is becoming a cornerstone in our concept of health. Colorectal cancer (CRC) prevention, in particular, has become an important goal for health providers, physicians and the general public. CRC fits the criteria of a disease suitable for chemopreventive interventions. It is a prevalent disease that is associated with considerable mortality and morbidity rates, with more than 1,000,000 new cases and 500,000 deaths expected, worldwide, in 2004. CRC has a natural history of transition from precursor to malignant lesion that spans, on average, 15-20 years, providing a window of opportunity for effective interventions and prevention. A pre-malignant precursor lesion (i.e. adenoma) usually precedes cancer, and helps to identify a subset of the population that is at increased risk of harbouring and developing cancer. Science and technology have evolved to a point where we are able to use our knowledge of cancer biology to identify individuals at risk and interrupt the process of malignant transformation at the level of the pre-cancerous lesion. Recent progress in molecular biology and pharmacology enhances the likelihood that cancer prevention will increasingly rely on chemoprevention. Chemoprevention, a new emerging science, means the use of agents to inhibit, delay or reverse carcinogenesis. Recent observations suggest a number of potential targets for chemoprevention. Many agents have potential benefit but only modest chemopreventive efficacy in clinical trials. There is much evidence suggesting an inverse relationship between aspirin or non-steroidal anti-inflammatory drug (NSAID) consumption and CRC incidence and mortality. However, NSAID consumption is not problem-free; 1997 data show 107,000 hospitalisations and 16,500 deaths due to NSAID consumption in the U.S. alone. Therefore, although chemoprevention of CRC is already possible, drugs that have more acceptable side-effect profiles than the currently available NSAIDs are required. Cyclo-oxygenase (COX)-2-specific inhibitors, which have an improved safety profile compared to traditional NSAIDs that inhibit both the COX-1 and COX-2 enzymes, seem to be well-suited drug candidates for CRC prevention. The inhibition of the growth of pre-cancerous and cancerous cells without affecting normal cells is the ultimate aim of cancer treatment and is of particular importance in chemoprevention studies, which may be long term in nature, involving healthy subjects and minimal toxicity. Cancer prevention is certain to be a significant focus of research and intervention in the coming years, propelled by the realisation that we will be able to identify both individuals susceptible to specific cancers as well as the molecular targets that can alter or stop the carcinogenesis process. Pharmacology and genetics are collaborating to develop new chemoprevention agents designed to affect molecular targets linked to specific premalignant or predisposing conditions.

Anti-Inflammatory Agents, Non-Steroidal↗