sulindac and Colorectal-Neoplasms

The onset of colorectal adenomas (CRAs) is significantly associated with colorectal cancer. The preventive effects of chemical drugs on the recurrence of CRAs have been evaluated in a large number of randomized controlled trials (RCTs). However, there are still uncertainties about the relative effectiveness of such chemical drugs.. We searched relevant RCTs published in six databases up to February 2023. The quality of the included studies was assessed by using the Cochrane risk of bias assessment tool and Review Manager 5.4. Pairwise comparison and network meta-analysis (NMA) were conducted using RStudio to compare the effects of chemical drugs on the recurrence of CRAs.. Forty-five high-quality RCTs were included. A total of 35 590 (test group: 20 822; control group: 14 768) subjects with a history of CRAs have been enrolled and randomized to receive placebo treatment or one of 24 interventions. Based on surface under the cumulative ranking values and NMA results, difluoromethylornithine (DFMO) + Sulindac significantly reduced the recurrence of CRAs, followed by berberine and nonsteroidal antiinflammatory drugs.. DFMO + Sulindac is more effective in reducing the recurrence of CRAs but has a high risk of adverse events. Considering drug safety, tolerance, and compliance, berberine has a brighter prospect of clinical development. However, further studies are needed to verify our findings.

Topics: Adenoma; Berberine; Colorectal Neoplasms; Humans; Network Meta-Analysis; Randomized Controlled Trials as Topic; Sulindac

Colorectal cancer is a common and often fatal malignancy. Currently, the modifications that alter disease outcome include early symptom recognition, population screening as well as improved surgical and adjuvant treatments. Preventative strategies have been limited with little evidence that lifestyle changes significantly alter risk. There is however a growing awareness of a potential role for chemoprevention in some patient groups. This study aimed to review the literature associated with chemoprevention in colorectal cancer.. An electronic literature search of MEDLINE and Embase databases was performed on PubMed for studies detailing the use of chemoprevention agents in colon and rectal cancer. The search was limited to clinical trials on adult humans (>16 years of age) published in English since 1990.. The strongest evidence is for non-steroidal anti-inflammatory drugs slowing polyp progression, notably Sulindac and aspirin in patients with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, respectively. There is also increasing evidence that continuing use of low-dose aspirin reduces long-term incidence of colorectal cancers. Cyclooxygenase 2 inhibitors also have a potential role but cardiac toxicity currently limits their use. Folic acid, statins, antioxidants, calcium and 5-aminosalicylic acid lack evidence to support their use at present.. Currently, there is not enough evidence to support the implementation of a chemopreventative agent for general use. However, there appears to be a role for aspirin in selected subgroups.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cardiotoxicity; Chemoprevention; Clinical Trials as Topic; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Cyclooxygenase 2 Inhibitors; Disease Progression; Humans; Incidence; Meta-Analysis as Topic; Middle Aged; Sulindac; Young Adult

Colorectal cancer (CRC) is presently one of the most common causes of cancer-related death in our setting and affects a great number of people each year. Screening strategies are commonly used but they do not seem enough to avoid CRC development or prevent completely its mortality. Because of this fact other prevention strategies have gained interest in recent years. Chemoprevention seems to be an attractive option in this setting and several drugs have been studied in this field. This review is focused on salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs) and cycloxygenase-2 inhibitors (COXIBs), whose mechanism of action could be directly related to colon cancer chemoprevention.

Topics: Adenoma; Adenomatous Polyposis Coli; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Celecoxib; Chemoprevention; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; Humans; Pyrazoles; Randomized Controlled Trials as Topic; Sulfonamides; Sulindac

To reduce the morbidity and mortality from colorectal cancer (CRC), current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients at risk for CRC. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with a sporadic or genetic risk of CRC. It will also discuss therapeutic end points under evaluation in current efforts to develop drugs for treating CRC risk factors.

Topics: Adenomatous Polyposis Coli; Antineoplastic Agents; Chemoprevention; Clinical Trials as Topic; Colonoscopy; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Eflornithine; Genetic Predisposition to Disease; Humans; Inflammatory Bowel Diseases; Neoplasm Recurrence, Local; Sulindac

Statins and nonsteroidal antiinflammatory drugs (NSAIDs) are commonly prescribed for lowering cholesterol and anti-inflammation, respectively. Recently, their potential roles as cancer chemopreventive agents have been subject to intensive studies. Human trials have not provided conclusive results on the protective effects of statins against different cancers, while more convincing results have been observed for cancer preventive effects of NSAIDs, especially on colorectal cancer. A promising strategy to enhance the cancer preventive efficacy of statins and NSAIDs is to use them in combination, which may produce synergy and lower the dose required for each agent. This strategy is of particular interest for potential use of low doses of statins and NSAIDs on a long-term basis for cancer chemoprevention; increased risks for gastrointestinal and cardiovascular side effects associated with the use of NSAIDs have been observed in colorectal cancer chemopreventive trials. This article reviews the evidence for the cancer preventive actions of statins and NSAIDs, as well as their possible synergistic action and the mechanisms involved.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Atorvastatin; Celecoxib; Colorectal Neoplasms; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Evidence-Based Medicine; Fatty Acids, Monounsaturated; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Lovastatin; Meta-Analysis as Topic; Neoplasms; Pravastatin; Pyrazoles; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Simvastatin; Sulfonamides; Sulindac

Topics: Adenoma; Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Carcinoma; Celecoxib; Colorectal Neoplasms; Evidence-Based Medicine; Humans; Meta-Analysis as Topic; Pyrazoles; Sulfonamides; Sulindac

Mortality in patients with advanced colorectal cancer(CRC) remains high. Epidemiologic studies show that individuals taking nonselective, nonsteroidal anti-inflammatory drugs, including aspirin, have a significant reduction in CRC mortality, compared with those not taking these agents. The recent characterization of cyclooxygenase- I and -2 (COX- I and COX-2) isoforms has led to an expanded understanding of how nonsteroidal anti-inflammatory drugs may help prevent polyp formation. Cyclooxygenase enzymes are required for the conversion of arachidonic acid to prostaglandins.COX-2 mediates the inflammatory effects of COX activity, is induced by a wide spectrum of growth factors and proinflammatory cytokines, and is overexpressed in numerous premalignant and malignant lesions, including CRC. Treatment with the selective COX-2 inhibitor celecoxib has shown promising results in the prevention of CRC, Numerous studies show that this COX-2 selective inhibitor is a potent suppressor of colon polyps both in animal models for familial adenomatous polyposis and in patients with this condition. This has led to the US Food and Drug Administration approval of celecoxib for the treatment of patients with familial adenomatous polyposis. The role of celecoxib in cancer treatment is still evolving. Recent studies have identified a potential benefit for adding celecoxib to standard CRC chemotherapy regimens to increase their efficacy and reduce their associated toxicity.

Topics: Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Clinical Trials as Topic; Colorectal Neoplasms; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Sulindac

In population-based observational studies, people had lower rates of colorectal cancer if they were taking various agents, including nonsteroidal anti-inflammatory drugs, calcium, and folate. In placebo-controlled trials in patients with familial adenomatous polyposis and in patients with sporadic colon adenomas, nonsteroidal anti-inflammatory drugs reduced the rates of adenomas, and there is a biologic rationale that they would be effective in reducing colorectal cancer as well. Randomized trials of chemopreventive agents are underway in the general population.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Celecoxib; Colorectal Neoplasms; Folic Acid; Humans; Pyrazoles; Sulfonamides; Sulindac

A NEW CONCEPT: Chemoprevention of cancer consists in the administration of chemical agents to prevent or inhibit carcinogenesis. This strategy can be applied at any stage of carcinogenesis.. The development of such agents relies on classical bases: phases I, II and III. The approach consists in assessing the effect of the substance tested in patients with history of resected adenomas of the colon and at high risk of relapse and/or family risk of colon cancer.. Are aspirin, type 2 cyclo-oxygenase inhibitors, calcium, folic acid, certain vitamins, hormone replacement therapy for menopausal women and difluoromethylornithine (DFMO).

Topics: Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Arthritis, Rheumatoid; Aspirin; Calcium, Dietary; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Controlled Clinical Trials as Topic; Cyclooxygenase Inhibitors; Dietary Supplements; Eflornithine; Enzyme Inhibitors; Female; Folic Acid; Hormone Replacement Therapy; Humans; Male; Mice; Mice, Knockout; Middle Aged; Risk Factors; Sulindac; Time Factors; Vitamins

Main purpose of the review is to analyse the impact of the current approaches for colorectal cancer prevention, including chemoprevention. Available evidence does not support the contention that a more appropriate diet can be of great help in the prevention of these neoplasms, either because the scientific evidence is poor and highly controversial, or because changes in diet are difficult to implement, at least in many Western countries. Similarly, a preventive approach based on the modification of lifestyle remains improbable, either in the short --or in the long period of time. Secondary prevention--i.e., the systematic removal of adenomatous polyps--can hardly be applied in the general population, with the exception of individuals at risk because members of families with Adenomatosis coli or Lynch syndrome, or affected by inflammatory bowel diseases. Finally, chemoprevention (i.e., the attempt to prevent tumour development through the administration of drugs or natural compounds that interfere with various phases of carcinogenesis) is still in its infancy Though attractive, this approach requires well-designed studies which should be carried out for years before being evaluated and interpreted; so far most of these investigations gave inconsistent or controversial results. In conclusion, both primary and secondary prevention of colorectal malignancies appear difficult to apply in the general population, and chemoprevention is still at the beginning of a (presumably] long story. The final impression is that notwithstanding the remarkable advancements made in the last two decades in colorectal cancer research, the practical application of these new concepts remains difficult.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Chemoprevention; Colorectal Neoplasms; Diet; Exercise; Folic Acid; Humans; Sulindac; Vitamins

It has been repeatedly observed that non-steroidal anti-inflammatory drugs, in particular sulindac and derivatives, may effectively prevent colorectal cancer. It has become apparent that exisulind (sulindac sulfone) induces apoptosis in tumor cells. Cell biological studies provided circumstantial evidence that the mechanism by which these agents exert their antitumor effect should be attributed to inhibition of cyclic-GMP phosphodiesterase (cGMP-PDE). The secondary increase of cGMP activates protein kinase G (PKG) and induces transcription of caspase genes, resulting in apoptosis. cGMP-PDEs comprise 11 gene families. Each family of PDEs is characterized by their ability to bind and degrade cAMP and cGMP but differs in physical and kinetic properties. Any single type of cell expresses a limited number of PDE-isoforms in order to regulate cGMP or cAMP levels. The majority of PDE inhibitors that have been investigated until now, except exisulind and a number of its analogs, do not induce apoptosis in tumor cells. Sulindac has a preventive effect on tumorigenesis in patients with polyposis of the colon. The anticancer effect of the novel sulindac derivatives has been demonstrated in over 50 different tumor cell lines, as well as in animal models of a variety of human cancers, such as mammary, prostate, lung and pancreatic carcinomas. Selective apoptotic antineoplastic drugs (SAANDs), as developed by Cell Pathways Inc, represent a novel class of anticancer agents that target a novel form of cGMP-PDE. It is believed that this enzyme is selectively increased in precancerous and cancerous cells. By specifically inhibiting the action of this particular cGMP-PDE, SAANDs enable various tumor cells to process an apoptotic signal and to commit suicide without affecting normal cells. As a result, side effects normally associated with traditional chemotherapeutic agents are not observed. One of the new compounds, CP-461, appeared < or = 100-fold more potent than exisulind in vitro. Studies of human cancer cell lines in vitro and dose-ranging phase I/II studies, both oral and iv, are discussed. Combinations of CP-461 with other chemotherapeutic agents are well tolerated.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Colorectal Neoplasms; Humans; Sulindac

Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of colorectal cancer. Moreover, the NSAID sulindac reduces the number and size of polyps in patients with familial adenomatous polyposis. The mechanisms of these effects of NSAIDs are not known but several lines of evidence suggest the involvement of the inhibition of the inducible isoform of prostaglandin H synthase (known as COX-2). Specific COX-2 inhibitors, showing an improved profile of gastrointestinal safety vis-à-vis conventional NSAIDs, provide interesting tools to probe the COX-2 dependence of the apparent protection against colorectal cancer associated with the use of NSAIDs.

Topics: Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Humans; Sulindac

The rate-limiting step in arachidonate metabolism is mediated by enzymes known as cyclooxygenases (COXs). These enzymes catalyze the biosynthesis of prostaglandin H2, the precursor of molecules such as prostaglandins, prostacyclin, and thromboxanes. The COX enzyme family consists of the classical COX-1 enzyme, which is constitutively expressed in many tissues, and a second isozyme, i.e., COX-2, which is induced by various stimuli, such as mitogens and cytokines, and is involved in many inflammatory reactions. Because nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2, these drugs also cause unwanted side effects, exemplified by gastrointestinal bleeding. Accumulating evidence indicates that NSAIDs can reduce the incidence of colorectal cancers in human and experimental animals and can reduce the number and size of polyps in patients with familial adenomatous polyposis. This Part II (of a two-part review) focuses on the growing clinical and experimental evidence that NSAIDS and COX-2 inhibitors can influence the risk of colon (and possibly of other) cancers.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Enzyme Induction; Humans; Isoenzymes; Membrane Proteins; Neoplasms; Neoplasms, Experimental; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Sulindac

The authors have presented a concise review of the studies which evaluate the risk of colorectal cancer among NSAID users. Animals studies have clearly documented a protective effect of NSAIDs in preventing colon cancers in a carcinogen-induced (AOM) model. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that they must be playing a role very early in the adenoma-to-carcinoma sequence of events. Several studies have indicated that treatment of FAP patients with NSAIDs causes a regression of adenomas that were already present prior to initiation of NSAID therapy. Many epidemiological studies have examined the relationship between aspirin use and colorectal cancer. Most of these studies have shown a marked decrease in the relative risk (40-50%) of colorectal cancer among continuous aspirin users. The appropriate dose and duration of aspirin treatment for optimal effects are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is their ability to inhibit cyclooxygenase. Presently, it is not clear whether inhibition of cyclooxygenase-1 or -2 effects on other signaling pathways are required for the protective effect of aspirin and other NSAIDs. The authors and others have demonstrated that COX-2 is upregulated from 2- to 50-fold in 85-90% of colorectal adenocarcinomas, which makes the COX-2 enzyme a possible target. Drugs are currently under development at several pharmaceutical companies that preferentially inhibit either COX-2 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, then these newly developed, more selective NSAIDs may play a role in future chemoprevention strategies.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Clinical Trials as Topic; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Humans; Incidence; Prospective Studies; Retrospective Studies; Sulindac; United States

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colonic Neoplasms; Colorectal Neoplasms; Humans; Sulindac

Topics: Adenocarcinoma; Adenomatous Polyps; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colorectal Neoplasms; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Male; Membrane Proteins; Mice; Prostaglandin-Endoperoxide Synthases; Randomized Controlled Trials as Topic; Sulindac

Gastrointestinal cancers are among the leading sites of cancer and leading causes of cancer-related deaths. Gastrointestinal cancers are often at an advanced stage at the time of diagnosis, and are highly resistant to non-surgical therapy. Thus early diagnosis and prevention are approaches that are under active investigation. Screening and surveillance are considered secondary prevention. Primary prevention is the use of dietary or environmental modification or chemopreventive agents. This written review will emphasize the potential role of acetylsalicylic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of gastrointestinal cancer, and specifically colorectal cancer. Cell culture and animal studies have shown that NSAIDs possess anti-proliferative and anti-neoplastic effects. Recent epidemiologic surveys also suggest that individuals who regularly take NSAIDs, particularly acetylsalicylic acid, have about a 50% decrease in colorectal cancer incidence and mortality. However, in the only interventional trial of aspirin (and beta-carotene), a retrospective analysis had inadequate statistical power to demonstrate any protective effect against colorectal cancer. About a dozen small prospective intervention studies have been done in a total of about a hundred patients with familial adenomatous polyposis to test the efficacy of NSAIDs, particularly sulindac. All human trials have shown substantial partial and some complete regression of colorectal and perhaps also duodenal adenomatous polyps. But virtually all patients had regrowth of adenomatous polyps after sulindac was stopped. In addition, sulindac and other NSAIDs result in occasional adverse events such as gastrointestinal bleeding. Thus sulindac cannot be recommended for routine use outside of a study setting. One valid current approach to the prevention of gastrointestinal cancer, and colorectal cancer in particular, is the adoption of a healthy lifestyle and appropriate screening and surveillance. Screening and surveillance guidelines have been developed by several public agencies and their recommendations should be adopted. In addition, we should adopt a healthy lifestyle and diet, which consists of low fat ( < 30% to total calories), and high fiber (> 3 daily servings of fruits/vegetables), with the avoidance of red meats ( < 3 weekly servings) and alcohol ( < 2 drinks daily), and the absolute avoidance of tobacco smoking.

Topics: Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Clinical Trials as Topic; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Epidemiologic Methods; Gastrointestinal Neoplasms; Humans; Sulindac

A concise review of the literature that evaluates the risk of colorectal cancer among NSAID users has been presented. Animal studies document a protective effect of NSAIDs in preventing colorectal cancers in carcinogen-induced (AOM) models and in Min mice. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that these agents must be acting early in the adenoma-to-carcinoma sequence. Treatment of FAP patients with NSAIDs causes regression of adenomas that were already present before initiation of therapy. Many epidemiologic studies have examined the relationship between aspirin use and colorectal cancer. Most show a marked decrease in the relative risk (40% to 50%) of this tumor among continuous aspirin users. The appropriate dose and duration of aspirin treatment needed for optimal results are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is inhibition of cyclooxygenase. Presently, whether inhibition of COX-1 or COX-2 is required for the protective effect of aspirin and other NSAIDs is unclear. The authors and others have demonstrated that COX-2 is up-regulated from 2 to 50 fold in 85% to 90% of colorectal adenocarcinomas, making the COX-2 enzyme a more likely target. The authors have also reported a dramatic increase in COX-2 expression in colon tumors that develop in rats after AOM treatment. Drugs are currently being developed that preferentially inhibit either COX-1 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, these newly developed, selective NSAIDs may play a role in future chemoprevention strategies.

Topics: Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aspirin; Case-Control Studies; Clinical Trials as Topic; Colorectal Neoplasms; Disease Models, Animal; Eicosanoids; Humans; Incidence; Mice; Prospective Studies; Rats; Retrospective Studies; Sulindac

Sulindac is useful in regression of adenomatous polyps. In addition to orally administered sulindac, rectal preparations also appear to be efficacious [32]. However, further studies are necessary to determine whether regression of adenomas, the precursor of colorectal cancer, will cause decrease in colorectal cancer risk in both FAP and non FAP patients. Moreover, clinical studies are needed to test the application of this potential chemopreventative drug in several other patient populations. Several interesting observations have been made concerning the use of sulindac. Indomethacin, a related NSAID to sulindac, did not cause polyp regression. Also, upper gastrointestinal tract polyps in the stomach and duodenum appear not to be affected by sulindac therapy. These observations might be explained by the metabolism of sulindac in which the pharmacologically active sulfide metabolite is generated and distributed in the large intestine. Also, investigators noted that after discontinuation of sulindac adenomas recurred. Sulindac treatment was well tolerated at the usual clinical doses. Although some investigators have speculated on the effect of prostaglandin inhibition sulindac on cAMP-dependent mechanisms which control cellular proliferation [33], the cause of adenoma regression is unknown. There is evidence that colorectal endogenous prostaglandin levels decrease with sulindac. Evaluation of colorectal mucosal cellular proliferation in patients treated with sulindac has revealed a decrease in labelling index by bromodeoxyuridine labeling in one study [28] but no change in labelling index by [3H]thymidine incorporation in another investigation [34]. Also, ki 67 labelling index, another measure of cellular proliferation, was not affected in the colorectal mucosa of patients taking sulindac.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenomatous Polyposis Coli; Animals; Anticarcinogenic Agents; Colorectal Neoplasms; Humans; Randomized Controlled Trials as Topic; Sulindac

Fascinating progress has been made in the past 2 years in our understanding of the genetic alterations associated with colorectal cancer predisposition and development. First, the genotype-phenotype relationship of the cancer susceptibility syndrome associated with familial adenomatous polyposis has been shown to depend on mutation type. Second, hereditary nonpolyposis colorectal cancer syndromes have been recognized as being frequently associated with a defect in the DNA mismatch-repair pathway. A gene on chromosome 2 called hMSH2, which demonstrates homology with the bacterial repair gene MutS, has been shown to be altered in some families with hereditary nonpolyposis colorectal cancer. A defect on chromosome 3 may act by impairing the same pathway. Genotyping of particular loci, termed microsatellite, provides an easy identification of tumors deficient in mismatch repair. Third, the mechanisms by which the inactivation of tumor-suppressor genes such as p53 and APC may contribute to the tumorigenic process have begun to be elucidated. These different discoveries will have important impacts in the prevention and management of colorectal carcinoma, one of the most frequent human cancers.

Topics: Adenomatous Polyposis Coli; Animals; Cell Transformation, Neoplastic; Chromosome Mapping; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 3; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA-Binding Proteins; DNA, Neoplasm; DNA, Satellite; Genes, APC; Genes, Tumor Suppressor; Genetic Predisposition to Disease; Humans; Mice; Mutation; MutS Homolog 2 Protein; Oncogenes; Proto-Oncogene Proteins; Sulindac; Syndrome

Patients with familial adenomatous polyposis (FAP) are at markedly increased risk for colorectal polyps and cancer. A combination of sulindac and erlotinib led to a 71% reduction in duodenal polyp burden in a phase 2 trial.. To evaluate effect of sulindac and erlotinib on colorectal adenoma regression in patients with FAP.. Prespecified secondary analysis for colorectal adenoma regression was carried out using data from a double-blind, randomized, placebo-controlled trial, enrolling 92 patients with FAP, conducted from July 2010 to June 2014 in Salt Lake City, Utah.. Patients were randomized to sulindac, 150 mg twice daily, and erlotinib, 75 mg daily (n = 46), vs placebo (n = 46) for 6 months.. The total number of polyps in the intact colorectum, ileal pouch anal anastomosis, or ileo-rectum were recorded at baseline and 6 months. The primary outcomes were change in total colorectal polyp count and percentage change in colorectal polyps, following 6 months of treatment.. Eighty-two randomized patients (mean [SD] age, 40 [13] years; 49 [60%] women) had colorectal polyp count data available for this secondary analysis: 22 with intact colon, 44 with ileal pouch anal anastomosis and 16 with ileo-rectal anastomosis; 41 patients received sulindac/erlotinib and 41 placebo. The total colorectal polyp count was significantly different between the placebo and sulindac-erlotinib group at 6 months in patients with net percentage change of 69.4% in those with an intact colorectum compared with placebo (95% CI, 28.8%-109.2%; P = .009).. In this double-blind, placebo-controlled, randomized trial we showed that combination treatment with sulindac and erlotinib compared with placebo resulted in significantly lower colorectal polyp burden after 6 months of treatment. There was a reduction in polyp burden in both those with an entire colorectum and those with only a rectal pouch or rectum.. clinicaltrials.gov Identifier: NCT01187901.

Topics: Adenomatous Polyposis Coli; Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Erlotinib Hydrochloride; Female; Humans; Male; Middle Aged; Sulindac; Treatment Outcome

Chemoprevention with the polyamine-inhibitory regimen difluoromethylornithine (DFMO) + sulindac markedly reduces risk of recurrent adenoma in colorectal adenoma patients. Obesity is associated with risk of colorectal adenoma and colorectal cancer. This study investigates how obesity influences risk of recurrent adenoma after prolonged treatment with DFMO + sulindac versus placebo.. Our analysis included subjects enrolled in the phase III colorectal adenoma prevention clinical trial investigating DFMO + sulindac versus placebo. Patients were classified by obesity (body mass index, BMI ≥ 30 kg/m(2)) status at baseline. Pearson χ(2) statistic and Mann-Whitney U test were used to compare baseline characteristics, including rectal tissue polyamine levels. Log-binomial regression analysis was used to determine the risk ratio (RR) of recurrent adenomas, adjusted for covariates and an interaction term for obesity and treatment.. The final analytic cohort was comprised of 267 patients. In separate regression models, the risk of adenoma recurrence after treatment compared to placebo was similar for obese (RR = 0.32, 95 % CI 15-71) and non-obese patients (RR = 0.27, 95 % CI 15-49). No significant interaction was detected between obesity, treatment, and risk of colorectal adenoma in the full regression model (p (interaction) = 0.91).. Obesity does not substantially modify the colorectal adenoma risk reduction ascribed to DFMO + sulindac versus placebo.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Double-Blind Method; Eflornithine; Female; Humans; Male; Middle Aged; Obesity; Placebo Effect; Polyamines; Regression Analysis; Sulindac; Treatment Outcome

Sulindac, atorvastatin, or prebiotic dietary fiber may reduce colorectal cancer (CRC) risk. However, clinical trial data are currently limited. We conducted a randomized, phase II chemoprevention trial involving subjects 40 years or older, with previously resected colon cancer or multiple/advanced colorectal adenomas. Magnification chromoendoscopy (MCE) was performed to identify and characterize rectal aberrant crypt foci (ACF); eligibility criteria required five or more rectal ACFs at baseline. Intervention assignments were as follows: (a) atorvastatin 20 mg qd; (b) sulindac 150 mg bid; (c) oligofructose-enriched inulin (as ORAFTI®Synergy1) 6 gm bid; or (d) control (maltodextrin) 6 gm bid, for 6 months. Percent change in rectal ACF number (%ΔACF) within arm was the primary endpoint. Secondary endpoints included changes in proliferation (Ki67) and apoptosis (caspase-3), as measured from normal mucosa biopsy samples. Among 85 eligible randomized subjects, 76 (86%) completed the trial per protocol. The median (range) of rectal ACF was 9 (5-34) and 8 (0-37) at baseline and postintervention, respectively. The median (SD) for %ΔACF was 5.6 (-69% to 143%), -18.6 (-83% to 160%), -3.6 (-88% to 83%), and -10.0 (-100% to 117%) in the atorvastatin, sulindac, ORAFTI®Synergy1 and control arms, respectively. Neither within-arm (P = 0.12-0.59) nor between-arm (P = 0.30-0.92) comparisons of %ΔACF were statistically significant. The active and control interventions also seemed to have similar effects on mucosal proliferation and apoptosis (P > 0.05 for each comparison). Data from this multicenter, phase II trial do not provide convincing evidence of CRC risk reduction from 6-month interventions with atorvastatin, sulindac, or ORAFTI®Synergy1, although statistical power was limited by the relatively small sample size.

Topics: Aberrant Crypt Foci; Aged; Antineoplastic Agents; Atorvastatin; Colorectal Neoplasms; Dietary Fiber; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intestinal Mucosa; Male; Middle Aged; Pyrroles; Sulindac; Survival Rate; Treatment Outcome

On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer.. Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted.. ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed.. ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer.

Topics: Aberrant Crypt Foci; Adenoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Polyps; Colorectal Neoplasms; Etodolac; Female; Humans; Male; Middle Aged; Sulindac

Combination of polyamine and prostaglandin E2 (PGE2)-synthesis inhibitors reduced the risk of colorectal adenoma (CRA) by 70% in patients who received polypectomies. We studied effects of the combination of difluoromethylornithine (DFMO) and sulindac on biomarkers and investigated factors that modify their efficacy.. We analyzed rectal mucosal levels of polyamines (spermidine, spermine, and putrescine) and PGE2, treatment regimens, and risk of CRA in 267 participants of a phase IIb/III chemoprevention trial of DFMO/sulindac.. In the group that received DFMO/sulindac, spermidine-to-spermine ratio (Spd:Spm) in rectal mucosa decreased between baseline and 12- and 36-month follow-up examinations (0.30, 0.23, and 0.24, respectively; P < .001 for both comparisons to baseline). Putrescine levels decreased between baseline and 12 months (0.46 vs 0.15 nmol/mg protein; P < .001) but rebounded between 12 and 36 months (0.15 vs 0.36 nmol/mg protein; P = .001). PGE2 levels did not change, although aspirin use was significantly associated with lower baseline levels of PGE2. No significant associations were observed between changes in biomarker levels and efficacy. However, drug efficacy was greatest in subjects with low Spd:Spm and high PGE2 at baseline; none of these subjects, versus 39% of those given placebo, developed CRA (P < .001). Efficacy was lowest in subjects with high Spd:Spm and low PGE2 at baseline; 28% developed CRA, compared with 36% of patients given placebo (P = .563).. A combination of DFMO and sulindac significantly suppressed production of rectal mucosal polyamines but not PGE2. No relationship was found between changes in biomarker levels and response. However, baseline biomarker levels modified the effect of DFMO/sulindac for CRA prevention.

Topics: Adenoma; Aged; Anticarcinogenic Agents; Biomarkers, Pharmacological; Biopsy; Colonoscopy; Colorectal Neoplasms; Dinoprostone; Double-Blind Method; Drug Therapy, Combination; Eflornithine; Enzyme Inhibitors; Female; Humans; Intestinal Mucosa; Likelihood Functions; Logistic Models; Male; Middle Aged; Neoplasms, Second Primary; Polyamines; Putrescine; Rectum; Spermidine; Spermine; Sulindac; Time Factors; Treatment Outcome

The ornithine decarboxylase-1 (ODC1) polymorphism at position +316 affects binding by transcriptional activators and repressors and modulates the risk of metachronous colorectal adenomas, particularly in association with aspirin use. We investigated the effects of ODC1 after treatment with difluoromethylornithine (eflornithine)/sulindac or placebo. Two hundred twenty-eight colorectal adenoma patients in a randomized phase III trial were genotyped for ODC1. We used Wilcoxon rank sums tests on non-normally distributed continuous variables across two genotype groups, χ(2) or Fisher exact test to assess the association between baseline categorical variables and genotype group, and log binomial regression for the primary (adenoma recurrence) and secondary outcomes (tissue polyamine response, cardiovascular toxicity, gastrointestinal toxicity, and ototoxicity). All statistical tests were two-sided. In binomial regression models with variables age, sex, race, aspirin use, treatment, and ODC1 genotype, treatment was the only statistically significant factor associated with differences in adenoma recurrence or tissue polyamine response. A statistically significant interaction was detected between ODC1 genotype and treatment with respect to adenoma recurrence (placebo group: GG, 50%, AA/GA: 34%; treatment group: GG, 11%, AA/GA, 21%; P(interaction) = .038). Excess ototoxicity was observed among ODC1 AA patients receiving treatment, but the interaction of genotype and treatment on ototoxicity was not statistically significant (P = .45).

Topics: Adenoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Confounding Factors, Epidemiologic; Eflornithine; Enzyme Inhibitors; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Proteins; Sulindac; Treatment Outcome

Nonsteroidal anti-inflammatory drugs (NSAID) have been associated with adverse cardiovascular (CV) outcomes in cancer prevention and other clinical trials. A recent meta-analysis suggested that baseline CV risk is associated with NSAID-associated adverse CV events. We evaluated the effect of baseline CV risk on adverse CV events in a phase III trial of difluoromethylornithine (DFMO) plus the NSAID sulindac versus placebo in preventing colorectal adenomas. Trial data were analyzed to determine baseline CV risk. CV toxicity outcomes were then assessed overall and excluding high CV-risk patients. Baseline CV risk scores were evenly distributed within our overall trial population of 184 placebo (low risk, 27%; moderate risk, 34%; high risk, 39%) and 191 DFMO/sulindac (low risk, 30%; moderate risk, 29%; high risk, 41%) patients. In patients with a high baseline CV risk, the number of adverse CV events was greater among DFMO/sulindac (n = 9) than among placebo (n = 3) patients. Excluding patients with a high baseline CV risk, the numbers of adverse CV events were similar in the DFMO/sulindac (n = 7) and placebo (n = 6) arms. A high CV risk score at baseline may confer an increased risk of CV events associated with treatment with DFMO/sulindac, and a low baseline score may not increase this risk. These results have implications for future NSAID-based cancer prevention clinical trials.

Topics: Adenoma; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Agents; Colorectal Neoplasms; Double-Blind Method; Drug Therapy, Combination; Eflornithine; Humans; Middle Aged; Placebos; Risk; Sulindac

Preclinical studies of chemoprevention drugs given in combination at low doses show remarkable efficacy in preventing adenomas with little additional toxicities, suggesting a strategy to improve risk to benefit ratios for preventing recurrent adenomas. Three hundred seventy-five patients with history of resected (> or =3 mm) adenomas were randomly assigned to receive oral difluoromethylornithine (DFMO) 500 mg and sulindac 150 mg once daily or matched placebos for 36 months, stratified by use of low-dose aspirin (81 mg) at baseline and clinical site. Follow-up colonoscopy was done 3 years after randomization or off-study. Colorectal adenoma recurrence was compared among the groups with log-binomial regression. Comparing the outcome in patients receiving placebos to those receiving active intervention, (a) the recurrence of one or more adenomas was 41.1% and 12.3% (risk ratio, 0.30; 95% confidence interval, 0.18-0.49; P < 0.001); (b) 8.5% had one or more advanced adenomas, compared with 0.7% of patients (risk ratio, 0.085; 95% confidence interval, 0.011-0.65; P < 0.001); and (c) 17 (13.2%) patients had multiple adenomas (>1) at the final colonoscopy, compared with 1 (0.7%; risk ratio, 0.055; 0.0074-0.41; P < 0.001). Serious adverse events (grade > or =3) occurred in 8.2% of patients in the placebo group, compared with 11% in the active intervention group (P = 0.35). There was no significant difference in the proportion of patients reporting hearing changes from baseline. Recurrent adenomatous polyps can be markedly reduced by a combination of low oral doses of DFMO and sulindac and with few side effects.

Topics: Adenoma; Adult; Aged; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Colonoscopy; Colorectal Neoplasms; Double-Blind Method; Eflornithine; Female; Humans; Male; Middle Aged; Placebos; Sulindac; Treatment Outcome

Sulindac is a nonsteroidal antiinflammatory drug with a chemopreventive effect in patients with familial adenomatous polyposis (FAP). In vivo, the active form of sulindac is sulindac sulfide, which is inactivated by the hepatic microsomal enzyme, flavin monooxygenase 3 (FMO3). In humans, numerous polymorphisms exist in FMO3, which alter enzymatic activity and subsequent substrate metabolism. We recently showed that certain polymorphic forms of FMO3 with reduced activity were associated with a more favorable response to sulindac in preventing the formation of adenomas in patients with FAP without polyps at baseline. Here, we determined whether these FMO3 polymorphisms correlated with the ability of sulindac to regress polyposis in patients with FAP who had polyps prior to treatment. Nineteen patients were treated with 150 mg sulindac twice a day for 6 months. The size and number of polyps in each patient was assessed at baseline (prior to the administration of sulindac), and at 3 and 6 months. Genotyping was done on seven established FMO3 polymorphisms with functional significance-M66I, E158K, P153L, V257M, E305X, E308G, and R492W. Statistical analyses were done with Wilcoxon rank sum test. Of the loci examined, only E158K and E308G showed polymorphic changes. Six patients exhibited polymorphisms in both E158K and E308G loci and were designated as genotype combination 1. The remaining patients were designated as genotype combination 2. Over the course of treatment, patients with genotype combination 1 had a greater reduction in both the size and number of polyps than those with genotype combination 2. These results suggest that combined polymorphic changes in the E158K and E308G alleles may protect against polyposis in patients with FAP treated with sulindac.

Topics: Adenoma; Adenomatous Polyposis Coli; Adenomatous Polyps; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Genotype; Humans; Oxygenases; Polymorphism, Genetic; Sulindac

Although sulindac is known to cause regression of colorectal adenomatous polyps in familial adenomatous polyposis, less is known about the effect of sulindac on sporadic adenomas. The precise mechanisms of these effects also remain to be determined.. Sulindac was given to patients with sporadic colorectal adenomatous polyps to evaluate its effects on them, and histological analysis was performed to elucidate the mechanism of the polyp regression, as well the kind of adenomatous polys that are susceptible to the agent.. 20 adenomatous polyps in 15 patients were studied.. Sulindac (300 mg daily) was given for four months, followed by colonoscopy with removal of the residual polyps. Polyp size, degree of atypia, inflammatory cell infiltration in the polyps, and immunostaining for mutant p53 product were evaluated before and after treatment.. 13 of the 20 polyps shrank or disappeared. Patient sex, polyp location, size, degree of atypia, or p53 mutation did not affect the response, but polyps in older patients were more sensitive to sulindac. The degree of atypia or inflammatory cell infiltration was not affected by the treatment. A polyp containing a focal cancer was unresponsive.. Sulindac can cause regression of sporadic colorectal adenomatous polyps.

Topics: Adenomatous Polyps; Aged; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Male; Middle Aged; Mutation; Sulindac; Tumor Suppressor Protein p53

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Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Caco-2 Cells; Calcium Channel Blockers; Calcium Channels; Calcium Signaling; Cell Movement; Colorectal Neoplasms; Humans; Intracellular Calcium-Sensing Proteins; Membrane Proteins; Neoplasm Metastasis; Prodrugs; Sulindac

Adenomatous polyposis coli (APC) truncations occur in many colorectal cancers and are often associated with immune infiltration. The aim of this study was to determine whether a combination of Wnt inhibition with anti-inflammatory (sulindac) and/or proapototic (ABT263) drugs can reduce colon adenomas.. Colorectal cancer is one of the most common cancers worldwide with limited therapeutic options. APC and other Wnt signaling mutations occur in the majority of colorectal cancers but there are currently no Wnt inhibitors in the clinic. The combination of Wnt pathway inhibition with sulindac provides an opportunity for killing

Topics: Adenoma; Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colonic Neoplasms; Colorectal Neoplasms; Mice; Protein Serine-Threonine Kinases; Sulindac

NSAIDs such as celecoxib and sulindac play a critical role in the treatment of colorectal cancer, yet it is not understood how sufficiently high concentrations are reached in colonic tissue. We previously demonstrated that an incomplete small intestinal absorption of celecoxib enables gut driven drug accumulation in caecal tissue, which is most likely needed for inducing remission. However, a multistage dissolution experiment suggested a more extensive absorption of sulindac relative to celecoxib, though still incomplete. To study whether caecal accumulation of sulindac is solely plasma driven or also gut driven, we performed an exploratory clinical study in healthy volunteers. After intake of a tablet of sulindac (200 mg; Arthrocine), two colonoscopies (1.0-2.5 h, and 6.0-7.5 h after drug intake) were performed to assess concentrations of sulindac and metabolites in plasma, caecal tissue and caecal contents. We observed that sulindac, even without the use of a colon-targeted delivery strategy, can arrive at the colonic lumen due to incomplete absorption and biliary excretion, and that the microbiota can catalyse the production of sulindac sulfide, which then accumulates in a high and local manner in the colonic tissue. These data can be relevant for drug development in the treatment of colorectal adenomas and cancer.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Colonic Neoplasms; Colorectal Neoplasms; Humans; Sulindac

Immune-checkpoint inhibitor (ICI) therapy has been widely used to treat different human cancers, particularly advanced solid tumors. However, clinical studies have reported that ICI immunotherapy benefits only ∼15% of patients with colorectal cancer, specifically those with tumors characterized by microsatellite instability (MSI), a molecular marker of defective DNA mismatch repair (dMMR). For the majority of patients with colorectal cancer who carry proficient MMR (pMMR), ICIs have shown little clinical benefit. In this study, we examined the efficacy of sulindac to enhance the response of pMMR colorectal cancer to anti-PD-L1 immunotherapy. We utilized a CT26 syngeneic mouse tumor model to compare the inhibitory effects of PD-L1 antibody (Ab), sulindac, and their combination on pMMR colorectal cancer tumor growth. We found that mice treated with combination therapy showed a significant reduction in tumor volume, along with increased infiltration of CD8

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Immunological; B7-H1 Antigen; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; DNA Mismatch Repair; Humans; Immune Checkpoint Inhibitors; Lymphocytes, Tumor-Infiltrating; Mice; NF-kappa B; Signal Transduction; Sulindac; Tumor Burden

Distant metastatic colorectal cancer (CRC) is present in approximately 25% of patients at initial diagnosis, and eventually half of CRC patients will develop metastatic disease. The 5-year survival rate for patients with metastatic CRC is a mere 12.5%; thus, there is an urgent need to investigate the molecular mechanisms of cancer progression in CRC. High expression of human high-mobility group A2 (HMGA2) is related to tumor progression, a poor prognosis, and a poor response to therapy for CRC. Therefore, HMGA2 is an attractive target for cancer therapy. In this study, we identified aspirin and sulindac sulfide as novel potential inhibitors of HMGA2 using a genome-wide mRNA signature-based approach. In addition, aspirin and sulindac sulfide induced cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration. Moreover, a gene set enrichment analysis (GSEA) revealed that gene sets related to inflammation were positively correlated with HMGA2 and that the main molecular function of these genes was categorized as a G-protein-coupled receptor (GPCR) activity event. Collectively, this is the first study to report that aspirin and sulindac sulfide are novel potential inhibitors of HMGA2, which can induce cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration through influencing inflammatory-response genes, the majority of which are involved in GPCR signaling.

Topics: Aspirin; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Cytotoxins; HMGA2 Protein; Humans; Neoplasm Proteins; Sulindac

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid.. As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apc. Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone.. Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.

Topics: Adenomatous Polyposis Coli Protein; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Colonic Polyps; Colorectal Neoplasms; Disease Models, Animal; Humans; Mice; Phospholipids; Sulindac

Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC.

Topics: Animals; Carcinogenesis; Colitis; Colitis, Ulcerative; Colon; Colorectal Neoplasms; Culture Media, Conditioned; Disease Models, Animal; HCT116 Cells; Humans; Inflammation; Interleukin-6; Macrophages; Mice; NF-kappa B; Retinoid X Receptor alpha; Signal Transduction; STAT3 Transcription Factor; Sulindac; TNF Receptor-Associated Factor 6

The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc. Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both.. The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.

Topics: Adenoma; Animals; Antineoplastic Agents; Atorvastatin; Colorectal Neoplasms; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Sulindac

Sulindac is an NSAID that can provide effective chemoprevention for colorectal cancer. In this study, alternative dosing regimens of sulindac were evaluated for their chemoprevention effectiveness in the azoxymethane-treated A/J mouse model of colorectal cancer. High-resolution endoscopic optical coherence tomography was utilized to time-serially measure tumor number and tumor burden in the distal colon as the biological endpoints. Four treatment groups were studied: (i) daily for 20 weeks (sulindac-daily); (ii) for 2 weeks, then no sulindac for 2 weeks, cycle repeated 5 times (sulindac-2); (iii) for 10 weeks ("on"), then no sulindac for 10 weeks ("off"; sulindac-10); and (iv) no sulindac (sulindac-none). Sulindac-2 and sulindac-daily had statistically significantly lower final tumor counts and slopes (change in number of tumors per week) when compared with sulindac-none (

Topics: Animals; Antineoplastic Agents; Azoxymethane; Carcinogens; Chemoprevention; Colorectal Neoplasms; Disease Models, Animal; Female; Mice; Sulindac

Expansion of a stem-like subpopulation with increased growth and survival potential is thought to drive colorectal tumor growth and progression. We investigated a CD44-positive (CD44((+))) subpopulation with extended growth and survival capacity in the human colon adenoma cell line LT97. This subpopulation expressed elevated levels of fibroblast growth factor 18 (FGF18) and fibroblast growth factor receptor FGFR3-IIIc. Expression levels of the FGFR3-IIIb, which does not bind FGF18, were similar in CD44((+)) and CD44((-)). Addition of FGF18 to the medium or its overexpression from an adenoviral vector increased the colony formation capacity of CD44((+)) threefold, and stimulated phosphorylation of ERK and GSK3β in both total LT97 populations and CD44((+)) cells. FGFR3 signaling blockade by expression of a dominant-negative FGFR3-IIIc mutant led to inhibition of both colony formation and down-stream signaling in the CD44((+)) cells. CD44((-)) cells did not respond. Blockade of the wnt-pathway by a dominant-negative Tcf4-mutant inhibited FGFR3 activation in LT97 cells as well as in HT29 colorectal cancer cells. The chemical wnt-inhibitor sulindac sulfide amide inhibited expression of FGF18 and FGFR3-IIIc and led to inhibition of receptor activation to less than 30% of control treated cells, both in LT97 and HT29 cultures. Our results demonstrate that an FGF18/FGFR3-IIIc autocrine growth and survival loop is up-regulated in a wnt-dependent manner and drives tumor cell growth in a subpopulation of colon adenoma cells. This subpopulation can be regarded as a precursor of colon cancer development and can be targeted for CRC-prevention by blocking either wnt- or FGFR3-signaling.

Topics: Adenoma; Antineoplastic Agents; Colon; Colorectal Neoplasms; Fibroblast Growth Factors; Humans; Hyaluronan Receptors; Receptor, Fibroblast Growth Factor, Type 3; Rectum; Signal Transduction; Sulindac; Wnt Proteins; Wnt Signaling Pathway

In the present study we have elaborated the putative mechanisms could be followed by the non-steroidal anti-inflammatory drugs (NSAIDs) viz. Sulindac and Celecoxib in the regulation of cell cycle checkpoints along with tumor suppressor proteins to achieve their chemopreventive effects in the initial stages of experimental colorectal cancer. Male Sprague-Dawley rats were administered with 1,2-dimethylhydrazine dihydrochloride (DMH) to produce early stages of colorectal carcinogenesis. The mRNA expression profiles of various target genes were analyzed by RT-PCR and validated by quantitative real-time PCR, whereas protein expression was analyzed by Western blotting. Nuclear localization of transcription factors or other nuclear proteins was analyzed by electrophoretic mobility shift assay and immunofluorescence. Flowcytometry was performed to analyze the differential apoptotic events and cell cycle regulation. Molecular docking studies with different target proteins were also performed to deduce the various putative mechanisms of action followed by Sulindac and Celecoxib. We observed that DMH administration has abruptly increased the proliferation of colonic cells which is macroscopically visible in the form of multiple plaque lesions and co-relates with the disturbed molecular mechanisms of cell cycle regulation. However, co-administration of NSAIDs has shown regulatory effects on cell cycle checkpoints via induction of various tumor suppressor proteins. We may conclude that Sulindac and Celecoxib could possibly follow p53/p21 mediated regulation of cell proliferation, where down regulation of NF-κB signaling and activation of PPARγ might serve as important additional events in vivo.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Binding Sites; Celecoxib; Cell Cycle Checkpoints; Cell Proliferation; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cyclooxygenase 1; Drug Administration Schedule; Male; Membrane Proteins; Molecular Docking Simulation; NF-kappa B; Protein Structure, Tertiary; Pyrazoles; Rats; Rats, Sprague-Dawley; Sulfonamides; Sulindac; Tumor Suppressor Protein p53; Up-Regulation

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well known for treating inflammatory disease and have been reported to have anti-tumorigenic effects. Their mechanisms are not fully understood, but both cyclooxygenase (COX) dependent and independent pathways are involved. Our goal was to shed further light on COX-independent activity.. Human colorectal cancer cells were observed under differential interference contrast microscopy (DICM), fluorescent microscopy, and micro-impedance measurement. Microarray analysis was performed using HCT-116 cells treated with sulindac sulfide (SS). PCR and Western blots were performed to confirm the microarray data and immunohistochemistry was performed to screen for Nesprin-2 expression. Micro-impedance was repeating including Nesprin-2 knock-down by siRNA.. HCT-116 cells treated with SS showed dramatic morphological changes under DICM and fluorescent microscopy, as well as weakened cellular adhesion as measured by micro-impedance. Nesprin-2 was selected from two independent microarrays, based on its novelty in relation to cancer and its role in cell organization. SS diminished Nesprin-2 mRNA expression as assessed by reverse transcriptase and real time PCR. Various other NSAIDs were also tested and demonstrated that inhibition of Nesprin-2 mRNA was not unique to SS. Additionally, immunohistochemistry showed higher levels of Nesprin-2 in many tumors in comparison with normal tissues. Further micro-impedance experiments on cells with reduced Nesprin-2 expression showed a proportional loss of cellular adhesion.. Nesprin-2 is down-regulated by NSAIDs and highly expressed in many cancers.. Our data suggest that Nesprin-2 may be a potential novel oncogene in human cancer cells and NSAIDs could decrease its expression.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Biomarkers, Tumor; Blotting, Western; Cell Adhesion; Cell Proliferation; Colorectal Neoplasms; Electric Impedance; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; Male; Microfilament Proteins; Nerve Tissue Proteins; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA Stability; RNA, Messenger; RNA, Small Interfering; Sulindac; Tissue Array Analysis; Tumor Cells, Cultured

This study aims to investigate the unclear molecular relationship involved in the activation of intrinsic pathway of apoptosis and NSAID-activated gene-1 (NAG-1) induction as a putative target in NSAIDs-mediated chemoprevention of colorectal cancer. Male Sprague-Dawley rats were administered with a colon-specific pro-carcinogen, 1,2-dimethylhydrazine dihydrochloride to achieve the early stages of colorectal cancer. Histopathological examination was performed for the analysis of neoplastic lesions while flow cytometry was performed for the relative quantification of intracellular reactive oxygen species (ROS), differential mitochondrial membrane potential (MMP or ΔΨ(M)), and apoptotic events. Various target biomolecules were analyzed either for their mRNA or protein expression profiles via RT-PCR and quantitative Real-Time PCR, or Western blotting and immunofluorescence, respectively. Enhanced gene as well as protein expression of pro-apoptotic agents was observed with the daily oral administration of two NSAIDs viz. Sulindac (cyclooxygenase (COX)-non-specific) and Celecoxib (a selective COX-2 inhibitor). A significant increase in early growth response-1 (EGR-1) protein expression and nuclear localization in NSAIDs co-administered animals may have positively regulated the expression of NAG-1 with a significant enhancement of intracellular ROS in turn decreasing the ΔΨ(M) to initiate apoptosis. In silico molecular docking analysis also showed that Sulindac and Celecoxib can block the active site pocket of B-cell lymphoma-extra large (Bcl-xL, anti-apoptotic transmembrane mitochondrial protein) which could be a putative mechanism followed by these NSAIDs to overcome anti-apoptotic properties of the molecule. NSAIDs-mediated up-regulation of EGR-1 and thereby NAG-1 along with implication of higher ROS load may positively regulate the intrinsic pathway of apoptosis for the chemoprevention of colorectal cancer.

Topics: 1,2-Dimethylhydrazine; Animals; Apoptosis; bcl-X Protein; Celecoxib; Colon; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; Early Growth Response Protein 1; Gene Expression; Growth Differentiation Factor 15; Male; Membrane Potential, Mitochondrial; Mitochondria; Molecular Docking Simulation; Pyrazoles; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sulfonamides; Sulindac

The protection against colorectal cancer (CRC) by non-steroidal anti-inflammatory drugs (NSAIDs) is in part dependent on inhibition of cyclooxygenase (COX). We compared the efficacy of the non-COX-inhibiting R-flurbiprofen (R-FB) with COX-inhibiting sulindac and racemic flurbiprofen (Rac-FB), and determined their effects on apoptosis, in an azoxymethane (AOM)-induced rat CRC model. In experiment 1, groups of rats were given a daily drug gavage (R-FB 30 mg/kg, Rac-FB 10 mg/kg and Sulindac 20 mg/kg) for one week, followed by AOM treatment and were sacrificed eight hours later, colons were examined for apoptosis and cell proliferation. In experiment 2, groups of rats were given two AOM treatments, followed by a daily drug gavage until they were sacrificed ten weeks later, and colons were examined for aberrant crypt foci (ACF) and prostaglandin E2 production. All drugs significantly enhanced apoptosis and inhibited ACF, irrespective of their COX-inhibiting potency (p<0.01), but sulindac was more potent in inhibition of large ACF, p<0.05. COX-inhibiting sulindac achieved the greatest protective effect. The greater safety profile of Rac-FB should provide an advantage for chemoprevention.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Azoxymethane; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Disease Models, Animal; Flurbiprofen; Male; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Sulindac

Initiation of various cancers has been observed to be regulated via a prolonged inflammatory state in the tissues. However, molecular role of such a localized inflammation is not clear in the advanced stages of colorectal cancer. In this study, we have elaborated the role of various pro- and anti-inflammatory cytokines, transcription, and angiogenic factors in the progression of the 1,2-dimethylhydrazine dihydrochloride (DMH)-induced late phage colorectal cancer and also observed the chemopreventive role of the two non-steroidal anti-inflammatory drugs (NSAIDs), viz., Sulindac and Celecoxib. Carcinogenic changes were observed with morphological and histopathological studies, whereas mRNA and protein regulations of various biomolecules were identified via RT- or qRT-PCR, western blot and immunofluorescence analysis, respectively. Activity of inducible nitric oxide (NO) and cyclooxygenase-2 enzymes were analyzed using standard NO assay and prostaglandin E2 immunoassay, whereas activities of matrix metalloproteinases (MMP-2 and-9) were identified by gelatin zymography. Flowcytometry was performed for the relative quantification of the apoptotic events. Molecular docking studies of Sulindac and Celecoxib were also performed with different target proteins to observe their putative mechanisms of action. As a result, we found that DMH-treated animals were having over-expression of various pro-inflammatory cytokines (IL-1β, IL-2, and IFNγ), aberrant nuclear localization of activated cell survival transcription factors (NF-κB and Stat3) along with the increased incidence of activated angiogenic factors (MMP-2 and MMP-9) suggesting a marked role of inflammation in the tumor progression. However, NSAIDs co-administration has significantly reduced the angiogenic potential of the growing neoplasm.

Topics: 1,2-Dimethylhydrazine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Celecoxib; Colorectal Neoplasms; Cyclooxygenase 2; Dinoprostone; Interferon-gamma; Interleukin-1beta; Interleukin-2; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; NF-kappa B; Nitric Oxide Synthase Type II; Pyrazoles; Rats; Rats, Sprague-Dawley; RNA, Messenger; STAT3 Transcription Factor; Sulfonamides; Sulindac

The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial.. Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75-100%) vs the lower three quartiles (0-25, 25-50 and 50-75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation.. A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1-3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08-0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53-4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates.. These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Diet; Eflornithine; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Polyamines; Prognosis; Sulindac; Survival Rate

Non-steroidal anti-inflammatory drugs (NSAIDs) have become promising agents for the chemoprevention of colorectal cancer presumably by inducing apoptosis. However, the role of NSAIDs in the regulation of NHE-1, intracellular calcium [Ca(2+)](i) homeostasis and Calpain 9 signaling pathway seems unclear. Male Sprague-Dawley rats were used as model for experimental colorectal cancer. Effects of pro-carcinogen (DMH) and NSAIDs were studied via morphological examination of tumors, histopathological changes, [Ca(2+)](i) homeostasis, production of reactive oxygen species (ROS), changes in mitochondrial membrane potential (MMP or ΔΨ(M)) and expression profile of target genes and proteins both at transcription and translation levels respectively. Size and number of tumors were found less in NSAIDs co-administered groups as compared to the DMH alone. Higher expression of NHE-1 was observed in DMH group whereas Calpain 9 was up-regulated in NSAIDs co-administered groups. [Ca(2+)](i) levels and reactive oxygen species were observed elevated in NSAIDs co-administered groups. ΔΨ(M) was found higher in DMH alone group along with the increased expression of the anti-apoptotic and mitochondrial membrane guard protein, Bcl-2. Expression levels of various pro-apoptotic proteins were observed higher in case of NSAIDs co-administered groups. Down-regulation of NHE-1, along with an increased [Ca(2+)](i) and induction of intrinsic pathway of apoptosis via activated Calpain 9 could be a putative mechanism pursued by Sulindac and Celecoxib for the chemoprevention of colorectal cancer.

Topics: 1,2-Dimethylhydrazine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Calcium; Calpain; Celecoxib; Colorectal Neoplasms; Down-Regulation; Gene Expression Regulation, Neoplastic; Male; Membrane Potential, Mitochondrial; Pyrazoles; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sodium-Hydrogen Exchangers; Sulfonamides; Sulindac; Up-Regulation

Nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) expression is upregulated not only by NSAIDs such as sulindac sulfide, but also by several antitumorigenic dietary compounds, suggesting that NAG-1 is a specific target for the development of effective anticancer agents. Despite being a downstream target of p53, NAG-1 induction is both p53-dependent and p53-independent. It is not clear whether NAG-1 induction is the responsible factor in cancer cell apoptosis with mutated p53. In this study, we report that NAG-1 induction alone cannot determine apoptotic cell fate in colon cancer cells. Although docetaxel induced an increase in NAG-1 and apoptosis in both HCT-116 (wild-type p53) and HT-29 (mutant p53) colon cancer cells, NAG-1 knockdown with siRNA prevented docetaxel-induced cell death in only HCT-116 cells. Docetaxel decreased Bcl-2 in HCT-116 cells, which have functionally active p53, according to luciferase reporter gene analyses, and docetaxel-induced cell death and changes in Bcl-2 and NAG-1 expression were blocked by PFT-α, a p53 inhibitor. In HT-29 cells with functionally inactive p53, the docetaxel-induced Bcl-xL decrease, NAG-1 increase, and cell death were not blocked by PFT-α. On the other hand, sulindac sulfide at concentrations that significantly induced NAG-1 did not decrease cell viability comparable to docetaxel, and it did not affect the level of p53, Bax, Bcl-2, and Bcl-xL in either cell line. The present study demonstrates that p53-dependent NAG-1 induction is linked to cell death and that NAG-1 induction without accompanying alteration of antiapoptosis protein Bcl-2 family members may not lead to cancer cell death.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Cell Survival; Colorectal Neoplasms; Docetaxel; Genes, p53; Growth Differentiation Factor 15; HCT116 Cells; HT29 Cells; Humans; Molecular Targeted Therapy; Sulindac; Taxoids; Tumor Suppressor Protein p53; Up-Regulation

Cancer chemoprevention strategies are not widely implemented in clinical practice. Targeting biomarkers in patients with elevated risk of developing cancer by means of short-term administration of certain agents may be a strategy to minimize toxicities while maintaining efficacy in clinical trials that can be completed in years rather than decades.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Agents; Biomarkers; Biomarkers, Tumor; Celecoxib; Chemoprevention; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; Humans; Pyrazoles; Sulfonamides; Sulindac

According to "fluid-mosaic model," plasma membrane is a bilayer constituted by phospholipids which regulates the various cellular activities governed by many proteins and enzymes. Any chemical, biochemical, or physical factor has to interact with the bilayer in order to regulate the cellular metabolism where various physicochemical properties of membrane, i.e., polarization, fluidity, electrostatic potential, and phase state may get affected. In this study, we have observed the in vivo effects of a pro-carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) and the two non steroidal anti-inflammatory drugs (NSAIDs); sulindac and celecoxib on various properties of the plasma membrane of colonocytes, i.e., electric potential, fluidity, anisotropy, microviscosity, lateral diffusion, and phase state in the experimentally induced colorectal cancer. A number of fluorescence probes were utilized like membrane fluidity and anisotropy by 1,6-diphenyl-1,3,5-hexatriene, membrane microviscosity by Pyrene, membrane electric potential by merocyanine 540, lateral diffusion by N-NBD-PE, and phase state by Laurdan. It is observed that membrane phospholipids are less densely packed and therefore, the membrane is more fluid in case of carcinogenesis produced by DMH than control. But NSAIDs are effective in reverting back the membrane toward normal state when co-administered with DMH. The membrane becomes less fluid, composed of low electric potential phospholipids whose lateral diffusion is being prohibited and the membrane stays mostly in relative gel phase. It may be stated that sulindac and celecoxib, the two NSAIDs may exert their anti-neoplastic role in colorectal cancer via modifying the physicochemical properties of the membranes.

Topics: 1,2-Dimethylhydrazine; 2-Naphthylamine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Celecoxib; Cell Membrane; Chemical Phenomena; Colorectal Neoplasms; Cyclooxygenase 2; Laurates; Male; Membrane Fluidity; Microscopy, Fluorescence; Phosphatidylethanolamines; Pyrazoles; Pyrimidinones; Rats; Rats, Sprague-Dawley; Spectrometry, Fluorescence; Sulfonamides; Sulindac; Viscosity

Growth-differentiation factor (GDF)-15, a member of the TGF-beta superfamily, is potently induced in the intestine following mechanical injury, genotoxic insult and following non-steroidal anti-inflammatory drugs (NSAIDs) exposure. GDF-15 expression correlates with apoptosis in intestinal cells and has been implicated in the pathogenesis of colorectal cancer formation and the anti-tumor effects of NSAIDs. We sought to determine the effect of loss of Gdf15 on animal tumor models of hereditary colon cancer and in the NSAID-mediated prevention of heritable colorectal cancer.. GDF-15 null (Gdf15 (-/-)) mice and mice with the genetic mutation found in hereditary poliposis coli, Apc ( min/+ ) were bred. Gdf15 ( -/- ), Apc ( min/+ ) and Gdf15 ( +/+ ), Apc ( min/+ ) mice were generated.. In Gdf15 ( -/- ), Apc ( min/+ ) mice, intestinal neoplasia formation rate and size were indistinguishable from that in Gdf15 ( +/+ ), Apc ( min/+ ) mice. Sulindac chemoprotection activity although potent in Gdf15 ( +/+ ), Apc ( min/+ ) mice was abolished in Gdf15 ( -/- ), Apc ( min/+ ) mice.. These results demonstrate in a murine model that GDF-15 does not significantly regulate heritable in vivo intestinal carcinogenesis but does mediate sulindac chemoprevention in heritable colon cancer. These data suggest that the use of GDF-15 activated signaling pathways may allow improved chemoprevention and therapies for colorectal cancer.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Colorectal Neoplasms; Disease Models, Animal; Genes, APC; Growth Differentiation Factor 15; Intestinal Neoplasms; Mice; Mice, Transgenic; Mutation; Sulindac

Toxicity and gastrointestinal side effects limits the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as agents to prevent colorectal cancer. These undesirable effects appear to be related to the inhibition of cyclooxygenase-associated pathways. Using the azoxymethane (AOM)-rat model of carcinogenesis, we aimed to test the potency of a low-toxicity R-flurbiprofen and whether NSAIDs have differing effects on regional tumor subtypes. Groups of 50 rats were gavaged 6 days a week with drug. After 1 and 2 wk on drug, rats were given intraperitoneal injection of AOM (15 mg/kg body wt). Groups were controls, sulindac (nonselective cyclooxygenase inhibitor) 5 and 20 mg/kg body wt per day, and R-flurbiprofen 30 mg/kg body wt per day. Tumor location, size, and histological subtype (either mucinous or nonmucinous) were recorded after 30 wk. The incidence of colon tumors was significantly reduced in the sulindac 20 mg (P < 0.001) and the R-flurbiprofen groups (P < 0.03) compared with the control group. The sulindac 20 mg and R-flurbiprofen groups also showed a reduced number of distal colon tumors (P < 0.03), whereas proximal tumors were not affected. Tumors only of the nonmucinous subtype were significantly reduced with the sulindac 20 mg and R-flurbiprofen groups (P < 0.001). Tumor size was not significantly different between all groups. Only the sulindac 20 mg group showed a reduced colonic prostaglandin E2 concentration. The sulindac groups showed a dose-dependant reduction in body weight gain (P < 0.001). In conclusion, R-flurbiprofen at a dose of 30 mg/kg body wt per day was well tolerated by the animals and, along with sulindac at 30 mg/day body wt, showed protection against the development of colon cancer in the rat-AOM model.

Topics: Animals; Antineoplastic Agents; Azoxymethane; Carcinogens; Colorectal Neoplasms; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Eicosanoids; Flurbiprofen; Male; Mucins; Rats; Rats, Sprague-Dawley; Sulindac

The use of sulindac sulfone (SFN) for colorectal cancer (CRC) therapy is limited due to its toxicity. The present study was carried out to examine whether curcumin, a novel chemopreventive agent, can potentiate the effects of low dosages of SFN in CRC treatment.. HT-29 CRC cells were exposed to SFN (200 - 400 microM), curcumin (5 - 10 microM) or their combination. The cytotoxic effects of the drugs were evaluated using growth inhibition assays. Annexin V/PI and cell cycle analysis were employed to study the mechanism of action of the drugs. The therapeutic efficacy of the drugs in vivo was examined using the aberrant crypt foci (ACF) model. The treatment groups included eight rats/group.. Treatment of cells with curcumin and SFN resulted in a synergistic inhibitory effect of 50 - 90% (p < 0.005) on cell growth. Growth inhibition was associated with inhibition of proliferation, G2/M arrest and induction of apoptosis. Administration of curcumin (0.6%) and SFN (0.06%) to 1, 2-dimethylhydrazine treated rats significantly reduced (by 75%, p < 0.01) the number of ACF.. Curcumin augments the therapeutic effects of SFN. This may be clinically important since the addition of curcumin to low dosages of SFN may encourage a safer and potent combinatorial treatment regimen for CRC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Cell Proliferation; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Drug Synergism; HT29 Cells; Humans; Male; Precancerous Conditions; Rats; Rats, Wistar; Sulindac

Nonsteroidal anti-inflammatory drugs (NSAID) are promising chemopreventive agents against colon and other cancers. However, the molecular basis mediated by NSAIDs for chemoprevention has not been fully elucidated. Environmental carcinogens induce DNA mutation and cellular transformation; therefore, we examined the effect of NSAIDs on carcinogenesis mediated by the aryl hydrocarbon receptor signaling pathway. In this study, we investigated the activities of a new class of NSAIDs containing dithiolethione moieties (S-NSAID) on both arms of carcinogenesis.. We investigated the effects of the S-NSAIDs, S-diclofenac and S-sulindac, on carcinogen activation and detoxification mechanisms in human hepatoma HepG2 and human colonic adenocarcinoma LS180 cells.. We found that S-diclofenac and S-sulindac inhibited the activity and expression of the carcinogen activating enzymes, cytochromes P-450 (CYP) CYP1A1, CYP1B1, and CYP1A2. Inhibition was mediated by transcriptional regulation of the aryl hydrocarbon receptor (AhR) pathway. The S-NSAIDs down-regulated carcinogen-induced expression of CYP1A1 heterogeneous nuclear RNA, a measure of transcription rate. Both compounds blocked carcinogen-activated AhR from binding to the xenobiotic responsive element as shown by chromatin immunoprecipitation. S-diclofenac and S-sulindac inhibited carcinogen-induced CYP enzyme activity through direct inhibition as well as through decreased transcriptional activation of the AhR. S-sulindac induced expression of several carcinogen detoxification enzymes of the glutathione cycle including glutathione S-transferase A2, glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione reductase.. These results indicate that S-diclofenac and S-sulindac may serve as effective chemoprevention agents by favorably balancing the equation of carcinogen activation and detoxification mechanisms.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Cell Line, Tumor; Colorectal Neoplasms; Cytochrome P-450 CYP1A1; Diclofenac; Humans; Liver Neoplasms; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; RNA, Messenger; Sulindac; Thiones

COX inhibitors appear to be promising agents in combination with cytostatics in the treatment of colorectal carcinoma (CRC). The aim of this study was to compare growth inhibitory effects of cytostatics (5-fluorouracil, 5-FU; oxaliplatin) and COX inhibitor sulindac sulfide (an active metabolite of sulindac), given alone or in combination, on several CRC cell lines.. A series of human CRC cell lines were incubated with various combinations of the test drugs used in concentrations from 3 to 200 microM. The cell survival was assessed by MTT assay. Isobolograms and median effect method of Chou and Talalay were used to assess the nature and quantitative aspects of interaction observed between studied drugs. Cell cycle progression and apoptosis were measured using flow cytometric methods. In addition, growth inhibitory effects of studied agents on CRC cell lines were compared with a normal (mouse fibroblast) cell line.. Sulindac sulfide synergistically potentiated the inhibitory effects of 5-FU and oxaliplatin on CRC survival, parallel to the induction of apoptosis. A dose reduction effect for synergistic activity of sulindac sulfide with studied cytostatics (in the range of 5- to 14-fold, when compared to single agent) suggested that the inhibitory effect of cytostatics on CRC survival may be obtained at low doses. In addition, sulindac sulfide appeared to be more specific against CRC cells than normal cells.. It was apparent that combination of 5-FU or oxaliplatin with sulindac sulfide results in a powerful inhibition of growth of colorectal carcinoma cells in vitro, which may be more specific for cancer than normal cells.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; BALB 3T3 Cells; Cell Cycle; Cell Growth Processes; Cell Survival; Colorectal Neoplasms; Drug Synergism; Fluorouracil; HT29 Cells; Humans; Mice; Organoplatinum Compounds; Oxaliplatin; Sulindac

To understand whether peroxisome proliferators-activated receptor-gamma (PPAR-gamma) plays an important role in the chemopreventive effect of sulindac on precancerous lesions (aberrant crypt foci, ACF) of rats.. Male Sprague-Dawley rats were used in this study and raised in Special Pathogen Free room. Sulindac was the main research object. Carcinogenic agent, 1, 2-dimethylhydrazine (DMH), was used to induce colonic precancerous lesions. Pioglitazone was chosen as agonist of PPAR-gamma and GW9662 used as a specific complete antagonist of PPAR-gamma. ACFs were induced according to the protocol certified in prior experiments. There were 7 groups, named as Negative control group, DMH group, Sulindac group, Sulindac+GW9662 group, Pioglitazone group, Pioglitazone+GW9662 group and GW9662 group. The experiment period was 12 weeks. At the end of the experiment, all rats were sacrificed by euthanasia. Half of the colon including the rectum was taken and immersed in formalin at 4 degrees Celsius overnight, and then recorded the number and size of ACF with the help of anatomic microscope stained by methylene blue.. (1) Sulindac and agonist of PPAR-gamma could significantly inhibit DMH-induced ACFs of rats from 137.8+/-59.4 to 73.9+/-32.1 and 96.4+/-32.6 with a decrease of 45.7% (P<0.01) and 30.0%(P<0.05) compared with DMH group. Antagonist of PPAR-gamma could counteract the chemopreventive effect of sulindac with an increase from 73.9+/-32.1 to 106.3+/-33.9; (2) The expression of PPAR-gamma in colorectal mucosa increased significantly during the DMH induction period compared with negative control group, the relative values of gray were 0.304+/-0.288 and 2.292+/-1.380 (P<0.01), sulindac and pioglitazone could decrease the expression of PPAR-gamma remarkably compared with DMH group, the relative values of gray were 1.023+/-1.115 and 0.352+/-0.187 (P<0.01), and the application of GW9662, antagonist of PPAR-gamma could promote the expression of PPAR-gamma in some degree, and the relative values of gray were 1.279+/-0.303 and 0.998+/-0.295 (P>0.05).. The expression of PPAR-gamma had risen in DMH-induced ACFs of rats significantly. Sulindac and agonist of PPAR-Gamma (pioglitazone) could inhibit the formation of ACF, and followed by a decrease of PPAR-gamma. Antagonist of PPAR-gamma could interfere with the effect of sulindac. PPAR-gamma might play an important role in the chemopreventive effect of sulindac on colorectal pre-cancerous lesions of rats and activation of PPAR-gamma pathway could inhibit the initiation and evolvement of ACF induced by DMH.

Topics: 1,2-Dimethylhydrazine; Anilides; Animals; Colorectal Neoplasms; Male; Pioglitazone; PPAR gamma; Precancerous Conditions; Rats; Rats, Sprague-Dawley; Sulindac; Thiazolidinediones

Topics: Adenoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Eflornithine; Humans; Neoplasm Recurrence, Local; Sulindac

Familial Adenomatous Polyposis (FAP) is a model for the adenoma-carcinoma sequence in several respects. One important area in which FAP serves as a model is chemoprevention. Early prevention trials mainly utilized micronutrients and were largely unsuccessful in preventing or causing regression of adenomas. A new era was ushered in by the recognition that antiarthritic doses of a nonsteroidal anti-inflammatory agent (NSAID), sulindac, could actually induce regression of colorectal adenomas in patients with FAP. Follow-up studies showed positive but variable long-term efficacy for colorectal adenomas, but sulindac appears to lack significant benefit in regressing duodenal adenomas or preventing initial occurrence of adenomas in APC mutation carriers. Due to the well-known side effects of traditional NSAIDs, selective COX-2 inhibitors have been studied rather extensively. Celecoxib has shown benefit in regressing colorectal adenomas and appears to have some duodenal activity as well. Rofecoxib, in smaller trials, showed efficacy as well. However, the entire field of NSAID research in chemoprevention is undergoing reexamination in light of recent demonstration of cardiovascular toxicity in nonfamilial or sporadic adenoma prevention trials. Whether NSAIDs will have a significant future in FAP chemoprevention will depend on a sober assessment of risks and benefits. These same issues will likely foster a more intensive search for new agents. FAP will undoubtedly continue to have a lead role in the testing of new agents, both in the interest of FAP management as such, and in anticipation of trials in nonfamilial adenomas, a problem with even greater societal impact. The historical development of chemoprevention in FAP will be presented, with an emphasis on issues of trial design.

Topics: Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Ascorbic Acid; Celecoxib; Chemoprevention; Clinical Trials as Topic; Colorectal Neoplasms; Curcumin; Cyclooxygenase 2 Inhibitors; Drug Therapy, Combination; Eflornithine; Humans; Lactones; Pyrazoles; Sulfonamides; Sulfones; Sulindac; Vitamins

Understanding the mechanisms that underlie the antitumour activity of non-steroidal anti-inflammatory drugs (NSAIDs) against colorectal cancer will allow the development of more effective and specific chemopreventative agents. Modulation of the NF-kappaB pathway has been implicated as a key effector of the antitumour effect of aspirin, but the effects of non-aspirin NSAIDs on this pathway have yet to be fully defined. Here, we demonstrate that sulindac, sulindac sulfone and indomethacin activate the NF-kappaB pathway in colorectal cancer cells, as determined by western blot analysis of cytoplasmic levels of IkappaBalpha and immunocytochemical analysis of nuclear NF-kappaB/RelA. Furthermore, we show that all of these NSAIDs induce nucleolar translocation of the RelA subunit of NF-kappaB. Using RelA deleted for the previously described nucleolar localization signal, we demonstrate that this response is causally involved in the apoptotic effects of these agents. Finally, we demonstrate that NSAID-mediated nucleolar translocation of RelA is associated with downregulation of NF-kappaB-driven transcription and of the NF-kappaB target gene, ICAM-1. These data identify nucleolar translocation of RelA and the associated repression of the NF-kappaB-driven transcription as a central molecular mechanism of NSAID-mediated growth inhibition and apoptosis. As well as providing new understanding of the molecular determinants of RelA function, these findings also have relevance to the development of novel chemotherapeutic and chemopreventative agents.

Topics: Active Transport, Cell Nucleus; Apoptosis; Cell Line, Tumor; Cell Nucleus; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Drug Screening Assays, Antitumor; Humans; Indomethacin; Sulindac; Transcription Factor RelA

Since recombinant human cyclooxygenase (COX) enzymes have been shown to activate environmental and dietary carcinogens implicated in human colorectal cancer etiology, we hypothesized that COX-2 inhibitors reduce arylamine-induced aberrant crypts (AC) and foci (ACF), preneoplastic lesions of colorectal cancer. Male weanling F344 inbred rats were fed modified AIN-76A control diet or the same diets supplemented with 320 ppm sulindac or 500, 1000, or 1500 ppm celecoxib. At 7 weeks of age, rats received a subcutaneous injection of 3,2'-dimethyl-4-aminobiphenyl (DMABP), an aryl-amine colon carcinogen, once weekly for two weeks. Ten weeks after the initial DMABP or vehicle treatment (at 17 weeks of age), rats were euthanized with CO(2), and the entire colorectum was removed and scored for ACF and AC. ACF possessing one to five AC were identified in the colorectum of rats administered DMABP, whereas no AC/ACF were identified in vehicle-treated controls. Significant reductions (p<0.001) in ACF and AC frequencies were observed in DMABP-treated rats supplemented with sulindac or celecoxib. Celecoxib reduced AC and ACF more than sulindac, but this difference was not significant (p>0.05). Reductions in both AC and ACF were highest following treatment with 1000 ppm celecoxib. These results provide additional experimental support for the chemopreventive effects of COX inhibitors in arylamine-induced colorectal cancer.

Topics: Aminobiphenyl Compounds; Animals; Anticarcinogenic Agents; Celecoxib; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Male; Pyrazoles; Rats; Rats, Inbred F344; Sulfonamides; Sulindac

Sulindac has been reported to be effective in suppressing tumor growth through the induction of p21WAF1/cip1 in human, animal models of colon cancer and colon cancer cells. In this study, we treated human breast cancer cell line MCF-7 and lung cancer cell line A549 as well as colon cancer cell line SW620 with sulindac to observe the effects of sulindac in other tissue sites. In all cell lines, proliferation was significantly inhibited by sulindac after 24 and 72 h of treatment. Apoptosis was induced by sulindac in both lung cancer cells and colon cancer cells but was not induced in breast cancer cells. Western blots showed that p21 protein level were induced by sulindac in lung cancer cells and colon cancer cells, but not in breast cancer cells. However, the suppression of beta-catenin, a key mediator of Wnt signaling pathway, was seen in all three cell lines with sulindac administration. Further studies revealed that transcriptional activities of beta-catenin were significantly inhibited by sulindac and that the inhibition was sulindac dosage-dependent. The transcriptional targets of beta-catenin, c-myc, cyclin D1 and cdk 4 were also dramatically downregulated. In conclusion, our data demonstrated that the efficacy of sulindac in the inhibition of cell proliferation (rather than the induction of apoptosis) might be through the suppression of beta-catenin pathway in human cancer cells.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; beta Catenin; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Luciferases; Lung Neoplasms; Proto-Oncogene Proteins c-myc; Sulindac; Transcription, Genetic; Transfection

To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3epsilon protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3epsilon proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 mumol/L inhibited 14-3-3epsilon protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3epsilon promoter activity. As 14-3-3epsilon promoter activation is mediated by peroxisome proliferator-activated receptor delta (PPARdelta), we determined the correlation between 14-3-3epsilon inhibition and PPARdelta suppression by NSAIDs. Sulindac sulfide inhibited PPARdelta protein expression and PPARdelta transcriptional activity. Overexpression of PPARdelta by adenoviral transfer rescued 14-3-3epsilon proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3epsilon suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPARdelta transduction. Stable expression of 14-3-3epsilon in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPARdelta/14-3-3epsilon transcriptional pathway. These results suggest that 14-3-3epsilon is a target for the prevention and therapy of colorectal cancer.

Topics: 14-3-3 Proteins; Adenoviridae; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; bcl-Associated Death Protein; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; HT29 Cells; Humans; Indomethacin; Mitochondria; PPAR delta; Promoter Regions, Genetic; Pyrazoles; Sulfonamides; Sulindac

Topics: Adenoma; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Female; Humans; Intestinal Polyposis; Middle Aged; Sulindac

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.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Chemoprevention; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Furans; Injections, Subcutaneous; Liver Neoplasms; Mice; Mice, Nude; Placebos; Random Allocation; Single-Blind Method; Sulindac

Non-steroidal anti-inflammatory drugs (NSAIDs) have shown chemopreventive properties in colorectal cancer, involving both cyclooxygenase (COX)-dependent and -independent mechanisms. Apart from their selectivity for COX isoenzymes, NSAIDs differ in their acidic character which supports ability to uncouple oxidative phosphorylation. To assess the possible contribution of uncoupling to their antineoplastic properties, we compared the effect of sulindac sulfide (SS), an acidic NSAID and NS-398, a non-acidic tricyclic, on mitochondrial function and apoptosis in colorectal cancer cell lines (HT29, Caco-2, HCT15 and HCT116). Although cell lines displayed a different COX status, SS and NS-398 caused growth arrest in a dose-related manner. High dose (10(-4)M) of SS but not of NS-398, increased the percentage of subG1 cell population while reducing mitochondrial transmembrane potential (DeltaPsim). Cyclosporin A (CsA, 1 microM) prevented collapse of DeltaPsim induced by 10(-4)M SS but not by 7.5 microM FCCP used as a protonophoric control. SS and FCCP increased the cytosolic release of Smac/DIABLO which was differently affected by CsA pretreatment depending on the uncoupler. Finally, 7.5 microM FCCP failed to induce apoptosis whereas CsA prevented apoptosis induced by SS from 16% in HCT15 to 41% in HCT116. The present study shows that despite the ability of sulindac sulfide to behave as a protonophoric uncoupler, CsA-sensitive opening of mitochondrial permeability transition pore contributes little to its pro-apoptotic effect in colorectal cancer cells.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Apoptosis Regulatory Proteins; Carrier Proteins; Chemoprevention; Colorectal Neoplasms; Humans; Intracellular Signaling Peptides and Proteins; Mitochondria; Mitochondrial Proteins; Nitrobenzenes; Oxidation-Reduction; Phosphorylation; Sulfonamides; Sulindac; Tumor Cells, Cultured; Uncoupling Agents

We previously showed that nonsteroidal anti-inflammatory drugs (NSAID) such as sulindac sulfide, which has chemopreventive activity, modulate the expression of several genes detected by microarray analysis. Activating transcription factor 3 (ATF3) was selected for further study because it is a transcription factor involved in cell proliferation, apoptosis, and invasion, and its expression is repressed in human colorectal tumors as compared with normal adjacent tissue. In this report, we show that ATF3 mRNA and protein expression are up-regulated in HCT-116 human colorectal cancer cells following treatment with NSAIDs, troglitazone, diallyl disulfide, and resveratrol. To ascertain the biological significance of ATF3, we overexpressed full-length ATF3 protein in the sense and antisense orientations. Overexpression of ATF3 in the sense orientation decreased focus formation in vitro and reduced the size of mouse tumor xenografts by 54% in vivo. Conversely, overexpression of antisense ATF3 was protumorigenic in vitro, however, not in vivo. ATF3 in the sense orientation did not modulate apoptosis, indicating another mechanism is involved. With microarray analysis, several genes relating to invasion and metastasis were identified by ATF3 overexpression and were confirmed by real-time reverse transcription-PCR, and several of these genes were modulated by sulindac sulfide, which inhibited invasion in these cells. Furthermore, overexpression of ATF3 inhibited invasion to a similar degree as sulindac sulfide treatment, whereas antisense ATF3 increased invasion. In conclusion, ATF3 represents a novel mechanism in which NSAIDs exert their anti-invasive activity, thereby linking ATF3 and its gene regulatory activity to the biological activity of these compounds.

Topics: Activating Transcription Factor 3; Allyl Compounds; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Chromans; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Disulfides; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Male; Mice; Mice, Nude; Microarray Analysis; Neoplasm Invasiveness; Resveratrol; RNA, Messenger; Stilbenes; Sulindac; Thiazolidinediones; Transcription Factors; Transplantation, Heterologous; Troglitazone; Up-Regulation

Expression of the gamma-glutamylcysteine synthetase heavy subunit (gamma-GCSh), which encodes the rate-limiting enzymes for glutathione biosynthesis, is regulated by many cytotoxic agents. Moreover, gamma-GCSh mRNA expression is elevated in colorectal cancer, but how gamma-GCSh expression is regulated is not completely understood. By using actinomycin D, which inhibits new RNA synthesis, we showed that treatment of human colorectal cancer cells with the prooxidant sulindac increased the half-life of gamma-GCSh mRNA. By using a tetracycline-regulated gamma-GCSh mRNA assay system, we systematically dissected the cis-acting sequence and trans-acting factors that regulate the stability of gamma-GCSh by cytotoxic prooxidants. We demonstrated that a HuR recognition sequence, AUUUA, in the 3'-untranslated region is responsible for the decay of gamma-GCSh mRNA. Oxidative stress enhanced cytoplasmic content of HuR. Overexpression of HuR by transfection stabilized gamma-GCSh mRNA, whereas overexpression of a dominant-negative HuR mutant suppressed the induced stability. Furthermore, prooxidant-induced gamma-GCSh mRNA stabilization and HuR binding were blocked by p38 mitogen-activated protein kinase inhibitors. We provide the first evidence that reduction-oxidation regulation of gamma-GCSh expression, itself a reduction-oxidation sensor and regulator, is mediated at least in part by the p38 mitogen-activated protein kinase signaling through the HuR RNA-binding protein.

Topics: Cell Line, Tumor; Colorectal Neoplasms; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutamate-Cysteine Ligase; Half-Life; Humans; MAP Kinase Signaling System; Oxidants; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Protein Subunits; Recombinant Proteins; RNA, Messenger; Sulindac

Sulindac reduces colorectal cancer risk in genetically susceptible humans and animals. The molecular mechanisms underlying these effects are incompletely understood. Many studies suggest an important role for induction of apoptosis involving the mitochondrial pathway and the death receptor pathway. Alternatively, mechanisms involving the APC-beta-catenin-Wnt pathway have been suggested, possibly mediated by p21. We determined the effects of sulindac on apoptosis and expression of death receptor (DR)-4 and DR5, beta-catenin, and p21 in normal-appearing colorectal epithelium. Biopsies were obtained before and after sulindac treatment during two chemoprevention studies. Patients (n = 18) with hereditary nonpolyposis colorectal cancer (HNPCC) received 150 mg sulindac bd for 4 weeks in a placebo-controlled crossover design. Patients (n = 6) with familial adenomatous polyposis (FAP) received 150 mg sulindac bd for 6 months. Apoptosis was assessed by M30 staining and expression patterns of DR4, DR5, beta-catenin, and p21 were studied immunohistochemically. In HNPCC patients, apoptotic indices were similar following placebo and sulindac. Also in FAP patients, apoptotic indices were not different after sulindac compared with pretreatment values. Expression of DR4 and DR5 was observed in all samples with no consistent differences between placebo/baseline and sulindac. Intensity of membranous beta-catenin staining was lower in HNPCC samples following sulindac compared with placebo (P < 0.001). Similar results were obtained in FAP samples (P < 0.01). p21 expressions before and after sulindac treatment were similar in both patient groups. In conclusion, sulindac inhibits beta-catenin expression in normal colorectal epithelium from HNPCC and FAP patients without affecting apoptotic indices and DR4, DR5, and p21 expression.

Topics: Adenomatous Polyposis Coli; Adult; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; beta Catenin; Biomarkers, Tumor; Colorectal Neoplasms; Cytoskeletal Proteins; Female; Humans; Male; Sulindac; Trans-Activators

Cyclooxygenase (COX) inhibitors have antitumorigenic activity and increase the expression of the early growth response gene Egr-1, a tumor suppressor gene and transcription factor. In this study, we have investigated the gene regulatory and anti-invasive activity of two traditional nonsteroidal anti-inflammatory drugs (NSAID), sulindac sulfide and indomethacin. These compounds inhibited tumor cell invasion and induced Egr-1 expression in lung adenocarcinoma A549 cells. Overexpression of Egr-1 reduced cellular invasion in the Matrigel system, whereas suppression of Egr-1 by small interference RNA (siRNA) attenuated the inhibition of Matrigel invasion by these compounds, indicating that Egr-1 is responsible for the decrease in invasion reported following treatment with NSAIDs. Egr-1-overexpressing cells were analyzed for genes involved in invasion and metastasis. Thrombospondin-1 (TSP-1) an antiangiogenic and anti-invasion protein was up-regulated by Egr-1 overexpression, which was confirmed following treatment with sulindac sulfide. Furthermore, the induction of TSP-1 by sulindac sulfide was blocked by Egr-1 siRNA. When TSP-1 was sequestered by the addition of anti-TSP-1 antibody, the inhibition of invasion by sulindac sulfide was attenuated, indicating that TSP-1 is involved in the inhibition of invasion by NSAIDs. We used the Min mouse model to determine if sulindac sulfide would increase Egr-1 and TSP-1 in vivo, because this model is widely used to study the effects of NSAIDs on tumor formation. Treatment of Min mice with concentrations of sulindac sulfide that inhibit tumor formation increased the expression of Egr-1 and TSP-1 in colonic tissues and in the polyps of these mice. This is the first report suggesting that COX inhibitors suppress tumor cell invasion via TSP-1, which occurs downstream of Egr-1.

Topics: Adenocarcinoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Early Growth Response Protein 1; Genes, Tumor Suppressor; Humans; Indomethacin; Lung Neoplasms; Mice; Neoplasm Invasiveness; RNA, Messenger; RNA, Small Interfering; Sulindac; Thrombospondin 1

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac have chemopreventive activity against colorectal tumors. Although the molecular mechanism has not been fully established, it is thought to involve the ability of NSAIDs to induce apoptosis. Because the majority of colon carcinomas are known to overexpress antiapoptotic proteins such as survivin and Bcl-2 and show only limited ability to undergo apoptosis, we hypothesized that the ability of sulindac to cause regression of adenomas and to inhibit colon carcinogenesis is mediated, at least in part, by down-regulation of one or more of these antiapoptotic proteins. To test this hypothesis, we exposed HT-29 colon carcinoma cells to sulindac. Sulindac induced a sustained decrease in mRNA and protein expression for survivin but not for Bcl-2. This finding suggests that sulindac is selectively acting through a survivin-related pathway. This is consistent with our earlier finding that inhibition of the beta-catenin:T-cell factor 4 (Tcf-4) pathway by the adenomatous polyposis coli protein down-regulates survivin expression and with recent evidence that sulindac induces beta-catenin degradation, which would reduce Tcf-4 activation. This suggests that the beta-catenin:Tcf-4:survivin mechanism may be a useful target for therapy or chemoprevention of colon cancer.

Topics: Antineoplastic Agents; Apoptosis; Colorectal Neoplasms; Gene Expression; HT29 Cells; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Sulindac; Survivin; Tumor Cells, Cultured

Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal anti-inflammatory drugs appear to inhibit the initial stages of the adenoma-carcinoma sequence, suggesting a link to the APC/beta-catenin/TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) beta-catenin and beta-catenin/TCF-mediated transcription was investigated. Nuclear beta-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on beta-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear beta-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated beta-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated beta-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear beta-catenin localisation and beta-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAIDs.

Topics: Adenoma; Adenomatous Polyposis Coli; Adult; Anti-Inflammatory Agents, Non-Steroidal; beta Catenin; Cell Nucleus; Cell Transformation, Neoplastic; Chemoprevention; Colorectal Neoplasms; Cytoskeletal Proteins; Female; Humans; Mitogens; Proto-Oncogene Proteins; Signal Transduction; Sulindac; Trans-Activators; Transcription, Genetic; Tumor Cells, Cultured; Wnt Proteins; Zebrafish Proteins

The adenomatous polyposis coli (APC) and mismatch repair (MMR) pathways are both involved in the tumorigenesis of hereditary colorectal cancers. Chemoprevention focuses on the APC pathway in the absence of information concerning MMR targets. This study compared the anticancer effects of sulindac, celecoxib, curcumin, and nifedipine in MMR-deficient cell lines, in order to determine the most appropriate chemopreventive agent for long-term use in patients with hereditary colorectal cancer.. Five human colorectal cell lines (SW480, HCT116, LoVo, SW48, and HCT15) and an endometrial cancer cell line (HEC-1-A) were used for susceptibility testing. Tests included assays for growth inhibition, cell-cycle arrest, and apoptosis.. Sulindac, celecoxib, curcumin, and nifedipine all displayed dose- and time-dependent anti-proliferation activities. Celecoxib was the most effective anti-proliferative agent, and increased the G0/G1 phase proportion in the cell cycle after treatment more significantly than the other agents in all cell lines. Curcumin displayed a more potent apoptosis-inducing activity than the other agents in treated cells.. The tested drugs were effective against colorectal and endometrial cancer cell lines. Celecoxib is more potent with fewer side effects than sulindac. Nifedipine's observed chemopreventive efficacy may complement its known therapeutic application in patients with hypertension.

Topics: Antineoplastic Agents; Apoptosis; Celecoxib; Cell Cycle; Cell Line, Tumor; Chemoprevention; Colorectal Neoplasms; Curcumin; Endometrial Neoplasms; Female; Humans; Nifedipine; Pyrazoles; Sulfonamides; Sulindac

The mechanism of the suppressive effect of nonsteroidal anti-inflammatory drugs in azoxymethan and dextran sulfate sodium-induced colonic aberrant crypt foci/tumors associated with chronic colitis in mice was studied. With administration of sulindac, a cyclooxygenase-1 and -2 inhibitor, the mean number of colonic aberrant crypt foci/tumors was significantly smaller than that of controls. There was no significant difference in prostaglandin E2 content in the colonic mucosa between the groups. Furthermore, nimesulid, a cyclooxygenase-2 selective inhibitor, also suppressed colonic aberrant crypt foci/tumors as well as sulindac. Administration of nimesulid caused apoptosis indices to be significantly higher along with cyclooxygenase-2 expression being significantly lower than in controls. Apoptosis indices of 400 ppm group of nimesulid were significantly higher than that of 200 ppm group. Nonsteroidal anti-inflammatory drugs distinctly suppress the occurrence of aberrant crypt foci/tumors in this murine colitis-associated neoplasia model. Induction of apoptosis is a more important factor for chemoprevention than this reduction of prostaglandin E2.

Topics: Animals; Apoptosis; Azoxymethane; Carcinogens; Chemoprevention; Chronic Disease; Colitis; Colon; Colonic Neoplasms; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Intestinal Mucosa; Male; Mice; Mice, Inbred CBA; Sulindac; Water Supply

The mechanisms underlying the anti-tumorigenic properties of cyclooxygenase inhibitors are not well understood. One novel hypothesis is alterations in gene expression. To test this hypothesis sulindac sulfide, which is used to treat familial adenomatous polyposis, was selected to detect gene modulation in human colorectal cells at physiological concentrations with microarray analysis. At micromolar concentrations, sulindac sulfide stimulated apoptosis and inhibited the growth of colorectal cancer cells on soft agar. Sulindac sulfide (10 microm) altered the expression of 65 genes in SW-480 colorectal cancer cells, which express cyclooxygenase-1 but little cyclooxygenase-2. A more detailed study of 11 genes revealed that their expression was altered in a time- and dose-dependent manner as measured by real-time RT-PCR. Northern analysis confirmed the expression of 9 of these genes, and Western analysis supported the conclusion that sulindac sulfide altered the expression of these proteins. Cyclooxygenase-deficient HCT-116 cells were more responsive to sulindac sulfide-induced gene expression than SW-480 cells. However, this response was diminished in HCT-116 cells overexpressing cyclooxygenase-1 compared with normal HCT-116 cells suggesting the presence of cyclooxygenase attenuates this response. However, prostaglandin E2, the main product of cyclooxygenase, only suppressed the sulindac sulfide-induced expression of two genes, with little known biological function while it modulated the expression of two more. The most likely explanation for this finding is the metabolism of sulindac sulfide to inactive metabolites by the peroxidase activity of cyclooxygenase. In conclusion, this is the first report showing sulindac sulfide, independent of cyclooxygenase, altered the expression of several genes possibly linked to its anti-tumorigenic and pro-apoptotic activity.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Blotting, Northern; Blotting, Western; Cell Division; Cell Separation; Cloning, Molecular; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dinoprostone; DNA; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Indomethacin; Isoenzymes; Membrane Proteins; Oligonucleotide Array Sequence Analysis; Prostaglandin-Endoperoxide Synthases; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulindac; Time Factors; Transcription, Genetic; Tumor Cells, Cultured

Naproxen, sulindac and salicylate, three NSAIDs (non-steroidal anti-inflammatory drugs), were cytotoxic to human colorectal cancer cells in culture. Toxicity was accompanied by significant depletion of intracellular polyamine content. Inhibition of ornithine decarboxylase (the first enzyme of the polyamine biosynthetic pathway), induction of polyamine oxidase and spermidine/spermine N(1)-acetyltransferase (the enzymes responsible for polyamine catabolism) and induction of polyamine export all contributed to the decreased intracellular polyamine content. Morphological examination of the cells showed typical signs of apoptosis, and this was confirmed by DNA fragmentation and measurement of caspase-3-like activity. Re-addition of spermidine to the cells partially prevented apoptosis and recovered the cell number. Thus polyamines appear to be an integral part of the signalling pathway mediating NSAID toxicity in human colorectal cancer cells, and may therefore also be important in cancer chemoprevention in humans.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Division; Cell Membrane; Cell Survival; Colorectal Neoplasms; DNA Fragmentation; Dose-Response Relationship, Drug; Fluorescent Dyes; Humans; Indoles; Intercalating Agents; Naproxen; Polyamines; Putrescine; Salicylates; Spermidine; Spermine; Sulindac; Tumor Cells, Cultured

To probe the risk of colorectal polyp, colon and rectal carcinoma and the intake of NSAIDs.. Case-control study participants were from patients who underwent colonoscopy at different hospitals, the persons with the above disease was as cases, and those without the above diseases was as controls. Use of NSAIDs was assessed by interviewing the participants with a questionnaire which include a list of NSAIDs and related dietary and life style factors and family history.. There are 37 cases of colorectal polyp, 105 cases of colon carcinoma and 142 cases of rectal carcinoma and 66 controls. Adjusted for potential confounders, the risk of colorectal polyposis, colon carcinoma and rectal carcinoma were markedly reduced by NSAIDs. The OR values were 0.21 (95% CI 0.07-0.65, P = 0.007), 0.13 (95% CI 0.05-0.35, P < 0.001), 0.15 (95% CI 0.11-0.58, P < 0.001) respectively. The risk of the above diseases were also reduced markedly by aspirin, the OR values were 0.265 (95% CI 0.07-0.96, P = 0.044), 0.10 (95% CI 0.03-0.35, P < 0.001), 0.15 (95% CI 0.04-0.49, P = 0.002) respectively. The risk of colon carcinoma was also reduced by profen, with the OR being 0.11 (95% CI 0.02-0.64, P = 0.014).. Aspirin and other NSAIDs could reduced the risk of colorectal polyp, colon carcinoma and rectal carcinoma markedly. Aspirin was the most prospective chemopreventive agents for colorectal polyp, colon and rectal carcinoma for its capability of reducing the risk of cardio-cerebral vascular disease as well.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colorectal Neoplasms; Female; Humans; Ibuprofen; Logistic Models; Male; Middle Aged; Piroxicam; Polyps; Rectal Neoplasms; Risk Factors; Sulindac; Time Factors

The mechanisms by which nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in colorectal cancer cells are undergoing intensive investigation. We found previously that NSAIDs induce apoptosis in these cells by restoring 15-lipoxygenase-1 (15-LOX-1) expression. The present study examined the NSAID mechanism for up-regulating 15-LOX-1 in two colorectal cancer cell lines (RKO and DLD-1). We found that NSAID effects on 15-LOX-1 occurred at the level of transcriptional regulation. We then studied NSAID effects on GATA-6, a transcription factor that suppresses 15-LOX-1 expression. Beginning within 4 h, NSAIDs progressively down-regulated GATA-6 expression. Ectopic GATA-6 expression blocked NSAID induction of 15-LOX-1 and apoptosis. NSAIDs down-regulate GATA-6 to transcriptionally up-regulate 15-LOX-1 and induce apoptosis in colorectal cancer cells.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Arachidonate 15-Lipoxygenase; Cell Division; Colorectal Neoplasms; DNA-Binding Proteins; GATA6 Transcription Factor; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Sulindac; Transcription Factors; Transcription, Genetic; Transfection; Tumor Cells, Cultured; Up-Regulation

The cornerstone of the systemic treatment of advanced colorectal cancer is 5-fluorouracil.However, 5-fluorouracil-induced apoptosis is dependent on p53, a tumor suppressor gene that is lost or inactivated in at least 85% of human colorectal cancers. Here we show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L triggers caspase-8-mediated truncation of BID, mitochondrial activation of caspase-9, and apoptosis in both p53(+/+) or p53(-/-) isogenic HCT116 colorectal cancer cells. TRAIL/Apo2L also sensitizes both p53(+/+) or p53(-/-) colorectal cancer cells to ionizing radiation. In contrast, we find that TRAIL/Apo2L fails to activate caspase-9 or induce apoptosis in isogenic HCT116 colorectal cancer cells that are deficient in BAX, a proapoptotic gene that is mutated in >50% of colorectal cancers of the microsatellite mutator phenotype. Loss of BAX also renders colorectal cancer cells resistant to TRAIL/Apo2L-mediated radiosensitization. We additionally demonstrate that TRAIL/Apo2L-induced death of p53(+/+)- or p53(-/-)- BAX-proficient but not BAX-deficient colorectal cancer cells is augmented by reducing nuclear factor-kappaB-dependent expression of Bcl-x(L) with either a peptide that disrupts the inhibitor of kappaB kinase complex or the nonsteroidal anti-inflammatory drug, sulindac sulfide. These results indicate that the combination of TRAIL/Apo2L with either irradiation or sulindac may be highly effective against both p53-proficient and p53-deficient colorectal cancers; however, BAX-deficient tumors may evade elimination by TRAIL/Apo2L-based regimens. Our findings may aid the development and genotype-specific application of TRAIL/Apo2L-based combinatorial regimens for the treatment of colorectal cancers.

Topics: Adenocarcinoma; Amino Acid Sequence; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; bcl-X Protein; Colorectal Neoplasms; Drug Synergism; Genes, p53; Humans; I-kappa B Kinase; Membrane Glycoproteins; Molecular Sequence Data; NF-kappa B; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Recombinant Proteins; Sulindac; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal carcinogenesis and prevent or revert the growth of premalignant colonic polyps. They inhibit cyclooxygenase (COX) but recent data indicate that this is not the only or even the most important mechanism of inhibition in colorectal tumor cells. We have used colonic carcinoma and adenoma cell lines to study the effects of the NSAID sulindac sulfide, its COX-inactive metabolite, sulindac sulfone, and the isoenzyme-specific inhibitors SC58125, SC236 and SC58560 on tumor cell growth in relation to COX-2 expression and prostaglandin production. To establish the role of COX-2 in NSAID action, we constructed clones expressing different levels of COX-2 from SW480 cells. All five compounds inhibited DNA synthesis and/or induced apoptosis, each with a characteristic pattern. ID(50)s were very similar in all the cell lines and were independent of COX expression, except for the COX-1 inhibitor SC58560, which was least effective in HT29/HI1, the cell line expressing the highest level of COX-1 (ID(50) 70 microM; in other cells lines the ID(50) was 15 microM). For all other compounds ID(50) concentrations varied less than two-fold: 25-40, 40-90 and 150 microM for SC236, sulindac sulfide and sulindac sulfone, respectively. SC58125 was the weakest inhibitor, never causing >50% cell loss. All compounds modulated expression of Bcl-2 and Bak and activated caspase 3. Overexpression of COX-2 in SW480 cells protected them against induction of apoptosis by sulindac sulfide. The effect was restricted to clones producing high levels of prostaglandin E(2). In summary, our data indicate that both COX-dependent and COX-independent mechanisms are involved in NSAID-induced growth in colorectal tumor cells. The concentrations necessary to inhibit growth were higher than serum concentrations that can be obtained in vivo, indicating that the therapeutic effect of NSAIDs cannot be explained by a direct effect of NSAIDs on the epithelial cells alone. For therapeutic purposes, compounds using different targets could be used to minimize side effects while optimizing therapeutic effect.

Topics: Adenoma; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma; Cell Division; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Growth Inhibitors; HT29 Cells; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Substrate Specificity; Sulindac; Tumor Cells, Cultured

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that have been implicated in a variety of biologic processes. The PPARdelta isotype was recently proposed as a downstream target of the adenomatous polyposis coli (APC)/beta-catenin pathway in colorectal carcinogenesis. To evaluate its role in tumorigenesis, a PPARdelta null cell line was created by targeted homologous recombination. When inoculated as xenografts in nude mice, PPARdelta -/- cells exhibited a decreased ability to form tumors compared with PPARdelta +/- and wild-type controls. These data suggest that suppression of PPARdelta expression contributes to the growth-inhibitory effects of the APC tumor suppressor.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Base Sequence; Cell Transformation, Neoplastic; Colorectal Neoplasms; DNA Primers; Humans; Receptors, Cytoplasmic and Nuclear; Sulindac; Transcription Factors; Tumor Cells, Cultured

Beta-catenin acts as a transcriptional coactivator by forming a complex with T-cell factor/lymphoid enhancer factor (TCF/LEF) DNA-binding proteins. Aberrant transactivation of a certain set of target genes by beta-catenin and TCF4 complexes has been implicated in familial and sporadic colorectal tumorigenesis. A colorectal cancer cell line, DLD-1, becomes irregularly multilayered, when maintained confluent for 2-3 weeks, and forms numerous dome-like polypoid foci piled-up over the surface of cell sheets. By the use of a strict tetracycline-regulation system, we found that the continuous suppression of beta-catenin/TCF4-mediated gene transactivation by dominant-negative TCF4B (deltaN30) reduced these piled-up foci and restored a simple monolayer of polarized columnar cells resembling normal intestinal epithelium. The restoration of epithelial cell polarity was evident in two ways: (a) the formation of microvilli over the apical surface; and (b) the distribution of a tight junction protein, ZO-1, to the lateral plasma membrane. Retroviral expression of stabilized beta-catenin (deltaN89) induced the formation of similar piled-up foci in untransformed IEC6 intestinal epithelial cells. Sulindac, a nonsteroidal antiinflammatory drug effective against colorectal tumorigenesis in familial adenomatous polyposis syndrome, suppressed the formation of foci. The loss of epithelial cell polarity may be a critical cellular event driving beta-catenin/TCF4-mediated intestinal tumorigenesis.

Topics: Adenocarcinoma; Amino Acid Sequence; Animals; Anti-Inflammatory Agents, Non-Steroidal; beta Catenin; Cell Division; Cell Membrane; Cell Polarity; Colorectal Neoplasms; Cytoskeletal Proteins; Doxycycline; Epithelial Cells; Genes, MDR; Humans; Intestinal Mucosa; Membrane Proteins; Molecular Sequence Data; Phosphoproteins; Rats; Retroviridae; Sulindac; TCF Transcription Factors; Trans-Activators; Transcription Factor 7-Like 2 Protein; Transcription Factors; Transcriptional Activation; Tumor Cells, Cultured; Zonula Occludens-1 Protein

To find out if nuclear morphometry is a useful indicator of prognosis in patients with familial adenomatous polyposis (FAP) before and after treatment with sulindac.. Open study.. Teaching hospital, Spain.. 29 patients (17 women and 12 men) with FAP who had been treated by colectomy. There were two control groups: 17 people with healthy rectal mucosa and 10 patients with colorectal cancer.. The 29 patients with FAP were treated with sulindac 150 mg orally twice daily for 6 months.. Results of histological examination of biopsy specimens and nuclear morphometry.. Before treatment, all patients with FAP had nuclei of cells in the rectal mucosa that were intermediate in size between those in healthy mucosa (small nuclei) and those in cancer (large nuclei). After 6 months' treatment with sulindac the patients with FAP no longer had any polyps and the size of the nuclei was similar to those in healthy mucosa. Only 1 patient failed to respond, and in this patient one of the polyps subsequently became malignant.. Nuclear morphometry may be useful in identifying patients with FAP who are at high risk of malignant degeneration.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Female; Humans; Intestinal Mucosa; Male; Rectum; Sulindac

We tried to elucidate the effects of sulindac on human colorectal carcinoma.. Sulindac (300 mg/day) was administered for two weeks before operation to 33 patients with sporadic colorectal carcinoma (Sulindac Group). Resected specimens were used to detect apoptosis by terminal dUTP nick end labeling and transforming growth factor (TGF)-beta1 expression by immunohistochemistry. The results were compared with those from the historical Control Group. Twenty-nine available preoperative biopsies taken from carcinomas before sulindac prescription and 22 concurrent colorectal adenomas (9 and 13 in Sulindac and Control Groups, respectively) in the resected specimen were also examined regarding TGF-beta1 expression.. In the resected carcinomas and adenomas, more frequent apoptosis and higher TGF-beta1 scores were observed in the Sulindac Group than in the Control Group. Overexpression of TGF-beta1 and apoptosis occurred in the same region in adenomas but not in carcinomas. A positive correlation between TGF-beta1 scores and apoptotic frequency was found in adenomas (P = 0.01, rho = 0.91) but not in carcinomas (P = 0.89, rho = 0.03).. We conclude that sulindac induces apoptosis in human colorectal carcinomas as well as in adenomas. Also, one of the antineoplastic effects of sulindac might be mediated by upregulating TGF-beta1 expression, particularly in colorectal adenomas.

Topics: Adenoma; Aged; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Carcinoma; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Preoperative Care; Sulindac; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

Epidemiological studies suggest that nonsteroidal anti-inflammatory agents decrease the risk of colorectal cancer. This is believed to be mediated, at least in part, by inhibition of cyclooxygenase (COX) activity. There are two COX isoenzymes, namely the constitutively expressed COX-1 and the inducible COX-2. COX-2 is overexpressed in adenomas and colorectal cancers, and COX-2-specific inhibitors have been shown to inhibit intestinal polyps in Apc(Delta716) mice more effectively than dual COX-1/COX-2 inhibitors such as sulindac. Various Apc knockout mice, including the multiple intestinal neoplasia (Min) mouse and the Apc(Delta716) mouse, are limited by their lack of large numbers of colonic adenomas and aberrant crypt foci, the putative precursors of large-bowel polyps and cancers. Our DNA mismatch-repair-deficient Min mouse model (Apc+/-Msh2-/-) has genetic features of both familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, and most importantly, rapidly develops numerous small- and large-bowel adenomas, as well as colonic aberrant crypt foci. The purpose of this study was to determine the effects of COX inhibitors on intestinal adenomas and colonic aberrant crypt foci in this accelerated polyposis, mismatch-repair-deficient Min mouse model, in addition to a standard Min mouse model. Weanling Apc+/-Msh2-/- and Min mice were fed diets containing no drug, sulindac, or a specific COX-2 inhibitor (MF-tricyclic). Apc+/-Msh2-/- and Min mice were sacrificed after 4 weeks and 5 months on diet, respectively. Apc+/-Msh2-/- mice treated with MF-tricyclic had significantly fewer small-bowel polyps (mean +/- SD, 178 +/- 29) compared with mice on sulindac (278 +/- 80), or control diet (341 +/- 43; P < 0.001). There was no difference in numbers of large-bowel polyps or aberrant crypt foci in mice in the three groups. MF-tricyclic was also effective in reducing both small- and large-bowel polyps in Min mice. Western analysis demonstrated COX-2 expression in both large- and small-bowel polyps from mice of both genotypes. This study demonstrates that a specific COX-2 inhibitor is effective in preventing small-bowel polyps in mismatch-repair-deficient Min mice and both small- and large-bowel polyps in standard Min mice. Therefore, specific COX-2 inhibitors may be useful as chemopreventive and therapeutic agents in humans at risk for colorectal neoplasia.

Topics: Adenoma; Animals; Colorectal Neoplasms; Crosses, Genetic; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; DNA Repair; DNA-Binding Proteins; Female; Furans; Genes, APC; Intestinal Polyps; Isoenzymes; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; MutS Homolog 2 Protein; Precancerous Conditions; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins; Substrate Specificity; Sulindac

Recent studies indicate that sulindac, a nonsteroidal anti-inflammatory drug (NSAID), lowers mucosal prostanoid levels and regresses colorectal adenomas in patients with familial adenomatous polyposis (FAP). To determine whether they are biomarkers for sulindac-mediated chemoprevention of colorectal adenomas, levels of 5 prostanoids [prostaglandin (PG) D2, PGE2, PGF2alpha, thromboxane B2, and 6-keto-PGF1alpha] in the normal-appearing rectal mucosa from 7 FAP patients with a history of subtotal colectomy and ileorectal anastomosis and 4 FAP patients without surgery, were measured in the absence or presence of exogenously added arachidonic acid before the initiation and at the end of 3 months of sulindac treatment. The addition of arachidonic acid resulted in a uniform increase in the levels of all 5 prostanoids although this increase was selectively attenuated in patients with ileorectal anastomosis who took sulindac. In the latter patients, arachidonic acid also augmented the inhibition of prostanoid synthesis by sulindac. In contrast, sulindac failed to attenuate the increase in prostanoid levels resulting from arachidonic acid in patients without previous surgery. Importantly, when measured in the presence of arachidonic acid, the reduction in the levels of all 5 prostanoids due to sulindac was statistically correlated with a reduction in the size and number of adenomas in the two groups of patients combined. These results suggest that tissue prostanoids measured in the presence of arachidonic acid may serve as sensitive and reliable biomarkers in monitoring the clinical responsiveness of FAP patients undergoing chemoprevention for colorectal neoplasia with NSAIDs.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers, Tumor; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Prostaglandins; Sulindac

Ileorectal anastomosis (IRA) is still used in the treatment of familial adenomatous polyposis (FAP). Sulindac appears to induce regression of colorectal adenomas; however, its effects in long-term therapy and in preventing carcinoma remain unclear.. Fifteen FAP patients treated by IRA received sulindac (200 mg/day) for a mean period of 48.6 +/- 28.7 (range 12-124) months. Number, size, and type of rectal polyps were assessed by endoscopic and histological evaluation every 6 months.. Significant regression of polyps was observed in all patients after 6 months (P < 0.02). However, after a mean of 48.6 +/- 28.7 months, both number and size of polyps increased again, showing no statistical difference with baseline values. Minute polyps appeared reddish, while the largest lesions were flat or slightly elevated. Endoscopic polypectomy was necessary in 9 patients and transanal surgical excision in 3. Two patients were submitted to restorative proctectomy because of a large polyp with severe dysplasia and a rectal cancer, respectively.. Sulindac appears to influence the morphological appearance of polyps in FAP patients, inducing apparent regression. However, at a dose of 200 mg, it does not influence the progression of polyps toward a malignant pattern.

Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Proctocolectomy, Restorative; Rectal Neoplasms; Sulindac

Nonsteroidal anti-inflammatory drugs (NSAIDs) appear to act via induction of apoptosis-programmed cell death-as potential colorectal cancer chemopreventive agents. NSAIDs can alter the production of different metabolites of polyunsaturated fatty acids (linoleic and arachidonic acids) through effects on lipoxygenases (LOXs) and cyclooxygenases. 15-LOX-1 is the main enzyme for metabolizing colonic linoleic acid to 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which induces apoptosis. In human colorectal cancers, the expression of this enzyme is reduced. NSAIDs can increase 15-LOX enzymatic activity in normal leukocytes, but their effects on 15-LOX in neoplastic cells have been unknown. We tested the hypothesis that NSAIDs induce apoptosis in colorectal cancer cells by increasing the protein expression and enzymatic activity of 15-LOX-1.. We assessed 15-LOX-1 protein expression and enzymatic activity, 13-S-HODE levels, and 15-LOX-1 inhibition in association with cellular growth inhibition and apoptosis induced by NSAIDs (primarily sulindac and NS-398) in two colorectal cancer cell lines (RKO and HT-29). All P values are two-sided.. Sulindac and NS-398 progressively increased 15-LOX-1 protein expression in RKO cells (at 24, 48, and 72 hours) in association with subsequent growth inhibition and apoptosis. Increased 13-S-HODE levels and the formation of 15-hydroxyeicosatetraenoic acid on incubation of the cells with the substrate arachidonic acid confirmed the enzymatic activity of 15-LOX-1. Inhibition of 15-LOX-1 in RKO cells by treatment with caffeic acid blocked NS-398-induced 13-S-HODE production, cellular growth inhibition, and apoptosis (P =. 007, P<.0001, and P<.0001, respectively); growth inhibition and apoptosis were restored by adding exogenous 13-S-HODE (P<.0001 for each) but not its parent compound, linoleic acid (P = 1.0 for each). Similar results occurred with other NSAIDs and in HT-29 cells.. These data identify 15-LOX-1 as a novel molecular target of NSAIDs for inducing apoptosis in colorectal carcinogenesis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apoptosis; Arachidonate 15-Lipoxygenase; Blotting, Western; Caffeic Acids; Colorectal Neoplasms; Cyclooxygenase Inhibitors; Gas Chromatography-Mass Spectrometry; Gene Expression Regulation, Neoplastic; Humans; Linoleic Acids; Nitrobenzenes; Sulfonamides; Sulindac; Tumor Cells, Cultured; Up-Regulation

To assess the role of BAX in drug-induced apoptosis in human colorectal cancer cells, we generated cells that lack functional BAX genes. Such cells were partially resistant to the apoptotic effects of the chemotherapeutic agent 5-fluorouracil, but apoptosis was not abolished. In contrast, the absence of BAX completely abolished the apoptotic response to the chemopreventive agent sulindac and other nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibited the expression of the antiapoptotic protein Bcl-XL, resulting in an altered ratio of BAX to Bcl-XL and subsequent mitochondria-mediated cell death. These results establish an unambiguous role for BAX in apoptotic processes in human epithelial cancers and may have implications for cancer chemoprevention strategies.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antimetabolites, Antineoplastic; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Colorectal Neoplasms; Fluorouracil; Genes, p53; Humans; Indomethacin; Intracellular Membranes; Membrane Potentials; Mitochondria; Mutation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogenes; Sulindac; Tumor Cells, Cultured; Tumor Suppressor Protein p53

The colonic epithelial cells near the top of the crypt and in the lumen have been shown to undergo apoptosis. Since butyric acid is the major short-chain fatty acid produced by fermentation of dietary fiber in the large bowel, it has been proposed that it could act as an important regulator of apoptosis in colorectal cancer. Here we report that in cells treated with butyric acid, the cleavage of DNA-PKcs was paralleled or preceded by the induction of activation of caspase-3, and these events were inhibited by Bcl-2 overexpression. We also demonstrated the redistribution of activated caspase-3 to the nuclear compartment where it locally cleaves DNA-PKcs and poly(ADP-ribose) polymerase, and cleaved fragments were released in the cytosolic compartment. The observed activation of caspase-3 and nuclear cleavage of its substrates and their subsequent release into the cytosol were inhibited by a specific caspase-3 inhibitor, the tetrapeptide DEVD-CHO. These findings suggest that relocalization of activated caspase-3 to the nucleus may constitute an important apoptotic signal during butyric acid-induction of apoptosis human colorectal cancer cells.

Topics: Apoptosis; Butyric Acid; Caspase 3; Caspase Inhibitors; Caspases; Catalytic Domain; Cell Nucleus; Colorectal Neoplasms; Cycloheximide; Cysteine Proteinase Inhibitors; Cytosol; DNA-Activated Protein Kinase; DNA-Binding Proteins; Enzyme Activation; Enzyme Precursors; Humans; Microscopy, Confocal; Molecular Weight; Nuclear Proteins; Poly(ADP-ribose) Polymerases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Sulindac; Tumor Cells, Cultured

Sulindac sulfide, a metabolite of the nonsteroidal antiinflammatory drug (NSAID) sulindac sulfoxide, is effective at reducing tumor burden in both familial adenomatous polyposis patients and in animals with colorectal cancer. Another sulindac sulfoxide metabolite, sulindac sulfone, has been reported to have antitumor properties without inhibiting cyclooxygenase activity. Here we report the effect of sulindac sulfone treatment on the growth of colorectal carcinoma cells. We observed that sulindac sulfide or sulfone treatment of HCA-7 cells led to inhibition of prostaglandin E2 production. Both sulindac sulfide and sulfone inhibited HCA-7 and HCT-116 cell growth in vitro. Sulindac sulfone had no effect on the growth of either HCA-7 or HCT-116 xenografts, whereas the sulfide derivative inhibited HCA-7 growth in vivo. Both sulindac sulfide and sulfone inhibited colon carcinoma cell growth and prostaglandin production in vitro, but sulindac sulfone had no effect on the growth of colon cancer cell xenografts in nude mice.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Blotting, Western; Cell Division; Chromatography, Gas; Collagen; Colorectal Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Dose-Response Relationship, Drug; Drug Combinations; Electrophoresis, Polyacrylamide Gel; Isoenzymes; Laminin; Membrane Proteins; Mice; Mice, Nude; Neoplasm Transplantation; Prostaglandin-Endoperoxide Synthases; Proteoglycans; Sulindac; Time Factors; Tumor Cells, Cultured

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colorectal Neoplasms; Humans; Risk; Sulindac

Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Colorectal Neoplasms; Humans; Sulindac

We have determined the dose-response relationship between sulindac administration and inhibition of tumour growth in the rat. The effect of tumour-inhibiting doses of sulindac on the production of prostaglandin E in tumours and macroscopically normal colon was then examined. Growth of pre-existing tumours was significantly reduced following administration of sulindac at 0.1 (P=0.004), 1 (P=0.01), 3 (P<0.001) and 10 mg/kg b.d. (P=0.002) for 4 weeks. There was no significant difference in prostaglandin E synthesis between tumours from control rats and those treated with sulindac at either 3 or 10 mg/kg b.d. (P=0.09 and 0.4, respectively). Prostaglandin E synthesis was reduced by 33 and 32% in macroscopically normal tissue from these treatment groups. These data show that sulindac inhibits tumour growth at low doses and do not support a role for the inhibition of prostaglandin synthesis, by sulindac, in the inhibition of tumour growth.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colon; Colorectal Neoplasms; Dose-Response Relationship, Drug; Indomethacin; Male; Prostaglandins; Rats; Rats, Sprague-Dawley; Sulindac

Topics: Adenomatous Polyposis Coli; Adult; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Sulindac

Sulindac, a non-steroidal anti-inflammatory drug, causes regression of colorectal adenomas in patients with familial adenomatous polyposis (FAP) but the response is variable. Specific clinical factors predictive of sulindac induced regression have not been studied.. 22 patients with FAP were given sulindac 150 mg orally twice a day. Polyp number and size were determined before treatment and at three months. The relation of nine clinical factors to polyp regression (per cent of baseline polyp number after treatment) was evaluated by univariate and multivariate analysis.. After three months of sulindac, polyp number had decreased to 45 per cent of baseline and polyp size to 50 per cent of baseline (p < 0.001 and p < 0.01, respectively). Univariate analysis showed greater polyp regression in older patients (p = 0.004), those with previous colectomy and ileorectal anastomosis (p = 0.001), and patients without identifiable mutation of the APC gene responsible for FAP (p = 0.05). With multivariate regression analysis, response to sulindac treatment was associated with previous subtotal colectomy.. Sulindac treatment seems effective in producing regression of colorectal adenomas of FAP patients with previous subtotal colectomy regardless of baseline polyp number and size. Changed sulindac metabolism, reduced area of the target mucosa, or changed epithelial characteristics after ileorectal anastomosis may explain these findings.

Topics: Adenomatous Polyposis Coli; Adenomatous Polyps; Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Remission Induction; Single-Blind Method; Sulindac

The Min mouse provides a genetically defined model for inherited and sporadic forms of human colorectal tumorigenesis. To test the suitability of this model for the evaluation and optimization of chemopreventive agents, we examined the effects of sulindac on tumorigenesis in Min mice as this compound can inhibit colorectal tumorigenesis in human familial adenomatous polyposis patients. Treatment of Min mice with sulindac in their drinking water (84 mg/l) or diet (167 and 334 p.p.m.) resulted in a significantly decreased average tumor load. The conservation of sulindac activity in the Min mouse provides an opportunity to explore the mechanism of sulindac suppression as well as to test other potential chemopreventive agents.

Topics: Adenomatous Polyposis Coli; Animals; Anticarcinogenic Agents; Colorectal Neoplasms; Disease Models, Animal; Humans; Mice; Mice, Mutant Strains; Sulindac

Environmental factors, particularly pertaining to the diet, are of importance in the pathogenesis of gastrointestinal neoplasia. Increasingly sophisticated studies have begun to elucidate some of the mechanisms responsible for both the deleterious and protective effects of compounds ingested or smoked (such as tobacco). The new and developing field of chemoprevention holds great promise for the possibility of averting neoplasia by interfering with the metabolism of carcinogens, reducing their binding to the target cell, or even by suppressing the initiated cell.

Topics: Antioxidants; Calcium; Colorectal Neoplasms; Dietary Fiber; Esophageal Neoplasms; Feeding Behavior; Female; Flavonoids; Gastrointestinal Neoplasms; Humans; Male; Stomach Neoplasms; Sulindac; Vitamins

First, and most importantly, the standard of care for treating adenomatous polyps is polypectomy and not therapy with NSAIDs. The initial clinical observation by Waddell and Loughry in 1983 that sulindac treatment influenced rectal polyps in patients with FAP has led to a considerable amount of research, commentary, and discussion during the past decade. These original observations have been validated by controlled clinical trials. Work presented in this issue by Ladenheim et al. indicates that sulindac may not be effective therapy for sporadic polyps that are present before initiation of treatment (secondary prevention). Even though their study may have failed to show a small effect of NSAIDs on polyps, further investigation of the ability of NSAIDs to cause regression of established polyps is probably not warranted. A more clinically relevant question, whether or not these agents can be used in a primary prevention strategy to prevent the development of adenomas in a colon devoid of these lesions, is currently being addressed in a large trial with sufficient statistical power to render firm conclusions (personal communication, January 1995). The multiple reports that sulindac treatment causes regression of adenomas in patients with FAP has stimulated research directed at understanding the molecular basis for these effects. If we are able to understand the molecular mechanism by which NSAIDs decrease the risk of colorectal cancer, we might be able to design more effective drugs or other approaches that would be clinically useful in humans for colorectal cancer chemoprevention.

Topics: Adenoma; Anti-Inflammatory Agents, Non-Steroidal; Colonic Polyps; Colorectal Neoplasms; Humans; Isoenzymes; Prostaglandin-Endoperoxide Synthases; Sulindac