Aspirin-induced nuclear translocation of NFκB and apoptosis in colorectal cancer is independent of p53 status and DNA mismatch repair proficiency

Substantial evidence indicates nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC). However, the molecular basis for this anti-tumour activity has not been fully elucidated. We previously reported that aspirin induces signal-specific IκBα degradation followed by NFκB nuclear translocation in CRC cells, and that this mechanism contributes substantially to aspirin-induced apoptosis. We have also reported the relative specificity of this aspirin-induced NFκB-dependent apoptotic effect for CRC cells, in comparison to other cancer cell types. It is now important to establish whether there is heterogeneity within CRC, with respect to the effects of aspirin on the NFκB pathway and apoptosis. p53 signalling and DNA mismatch repair (MMR) are known to be deranged in CRC and have been reported as potential molecular targets for the anti-tumour activity of NSAIDs. Furthermore, both p53 and MMR dysfunction have been shown to confer resistance to chemotherapeutic agents. Here, we set out to determine the p53 and hMLH1 dependency of the effects of aspirin on NFκB signalling and apoptosis in CRC. We specifically compared the effects of aspirin treatment on cell viability, apoptosis and NFκB signalling in an HCT-116 CRC cell line with the p53 gene homozygously disrupted (HCT-116p53−/−) and an HCT-116 cell line rendered MMR proficient by chromosomal transfer (HCT-116+ch3), to the parental HCT-116 CRC cell line. We found that aspirin treatment induced apoptosis following IκBα degradation, NFκB nuclear translocation and repression of NFκB-driven transcription, irrespective of p53 and DNA MMR status. These findings are relevant for design of both novel chemopreventative agents and chemoprevention trials in CRC

Therapeutic utility of aspirin in the Apc(Min/+) murine model of colon carcinogenesis

BACKGROUND: In recent years it has become evident that nonsteroidal anti-inflammatory drugs, in particular aspirin represent a potential class of cancer chemotherapeutic agents. Despite the wealth of knowledge gained from epidemiological, clinical and animal studies, the effectiveness of aspirin to treat established gastrointestinal cancer has not been determined. The present study examines the ability of aspirin to treat established polyposis in Min/+ mice. METHODS: Min/+ mice with established polyposis were treated orally once daily from 12–16 weeks of age with either drug vehicle or aspirin (25 mg/kg). Upon completion of treatment, the number, location and size of intestinal tumours was determined. Additional variables examined were the number of apoptotic cells within tumours and COX activity. RESULTS: Administration of aspirin for 4 weeks to Min/+ mice produce no effect on tumour number compared to vehicle-treated Min/+ mice (65 ± 8 vs. 63 ± 9, respectively). In addition, aspirin had no effect on tumour size or location. However, aspirin treatment produced a greater than 2-fold (p < 0.05) increase in the number of apoptotic positive cells within tumours and significantly decreased hepatic PGE(2) content. CONCLUSIONS: Aspirin was found to have no effect on tumour number and size when administered to Min/+ mice with established polyposis. The findings in the present study call in to question the utility of aspirin as a stand-alone treatment for established GI cancer. However, aspirin's ability to significantly promote apoptosis may render it suitable for use in combinatorial chemotherapy

Inhibition of haematogenous metastasis of colon cancer in mice by a selective COX-2 inhibitor, JTE-522

It is proposed that non-steroidal anti-inflammatory drugs (NSAIDs) reduce colorectal tumorigenesis by inhibition of cyclooxygenase (COX). COX is a key enzyme in the conversion of arachidonic acid to prostaglandins and two isoforms of COX have been characterized, COX-1 and COX-2. Multiple studies have shown that COX-2 is expressed at high levels in colorectal tumours and play a role in colorectal tumorigenesis. Recently it has been reported that selective inhibition of COX-2 inhibits colon cancer cell growth. In this study we investigated the effect of a selective COX-2 inhibitor (JTE-522) on haematogenous metastasis of colon cancer. For this purpose, we selected a murine colon cancer cell line, colon-26, that constitutively expresses the COX-2 protein. The subclone P expressed a high level of COX-2 and the subclone 5 expressed a low level. The colon-26 subclones were injected into the tail vein of BALB/c mice. JTE-522 was given intraperitoneally every day from the day prior to cancer cell injection, and the mice were sacrificed 16 days after cell injection. Lung metastases were compared between groups with and without JTE-522. In the mice injected with subclone P, the number of lung metastatic nodules was significantly reduced in the treated group. However, in the mice injected with subclone 5, there was little difference between the control and the treated groups. These results indicate that there may be a direct link between inhibition of haematogenous metastasis of colon cancer and selective inhibition of COX-2, and that selective COX-2 inhibitors may be a novel class of therapeutic agents not only for colorectal tumorigenesis but also for haematogenous metastasis of colon cancer. © 1999 Cancer Research Campaig

The utility of Aspirin in dukes C and high risk dukes B colorectal cancer - The ASCOLT study: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>High quality evidence indicates that aspirin is effective in reducing colorectal polyps; and numerous epidemiological studies point towards an ability to prevent colorectal cancer. However the role of Aspirin as an adjuvant agent in patients with established cancers remains to be defined. Recently a nested case-control study within the Nurses Health cohort suggested that the initiation of Aspirin <it>after </it>the diagnosis of colon cancer reduced overall colorectal cancer specific mortality. Although this data is supportive of Aspirin's biological activity in this disease and possible role in adjuvant therapy, it needs to be confirmed in a randomized prospective trial.</p> <p>Methods/Design</p> <p>We hypothesize through this randomized, placebo-controlled adjuvant study, that Aspirin in patients with dukes C or high risk dukes B colorectal cancer (ASCOLT) can improve survival in this patient population over placebo control. The primary endpoint of this study is Disease Free Survival and the secondary Endpoint is 5 yr Overall Survival. This study will randomize eligible patients with Dukes C or high risk Dukes B colorectal cancer, after completion of surgery and standard adjuvant chemotherapy (+/- radiation therapy for rectal cancer patients) to 200 mg Aspirin or Placebo for 3 years. Stratification factors include study centre, rectal or colon cancer stage, and type of adjuvant chemotherapy (exposed/not exposed to oxaliplatin). After randomization, patient will be followed up with 3 monthly assessments whilst on study drug and for a total of 5 years. Patients with active peptic ulcer disease, bleeding diathesis or on treatment with aspirin or anti-platelet agents will be excluded from the study.</p> <p>Discussion</p> <p>This study aims to evaluate Aspirin's role as an adjuvant treatment in colorectal cancer. If indeed found to be beneficial, because aspirin is cheap, accessible and easy to administer, it will positively impact the lives of many individuals in Asia and globally.</p> <p>Trials Registration</p> <p>Clinicaltrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00565708">NCT00565708</a></p

Widening of Socioeconomic Inequalities in U.S. Death Rates, 1993–2001

Background: Socioeconomic inequalities in death rates from all causes combined widened from 1960 until 1990 in the U.S., largely because cardiovascular death rates decreased more slowly in lower than in higher socioeconomic groups. However, no studies have examined trends in inequalities using recent US national data. Methodology/Principal Findings: We calculated annual age-standardized death rates from 1993–2001 for 25–64 year old non-Hispanic whites and blacks by level of education for all causes and for the seven most common causes of death using death certificate information from 43 states and Washington, D.C. Regression analysis was used to estimate annual percent change. The inequalities in all cause death rates between Americans with less than high school education and college graduates increased rapidly from 1993 to 2001 due to both significant decreases in mortality from all causes, heart disease, cancer, stroke, and other conditions in the most educated and lack of change or increases among the least educated. For white women, the all cause death rate increased significantly by 3.2 percent per year in the least educated and by 0.7 percent per year in high school graduates. The rate ratio (RR) comparing the least versus most educated increased from 2.9 (95 % CI, 2.8–3.1) in 1993 to 4.4 (4.1–4.6) in 2001 among white men, from 2.1 (1.8–2.5) to 3.4 (2.9–3–9) in black men, and from 2.6 (2.4–2.7) to 3.8 (3.6–4.0) in white women. Conclusion: Socioeconomic inequalities in mortality are increasing rapidly due to continued progress by educated whit

Determination of an optimal dosing regimen for aspirin chemoprevention of 1,2-dimethylhydrazine-induced colon tumours in rats

In order to establish an optimal timing and duration of aspirin treatment in the chemoprevention of 1,2-dimethylhydrazine (DMH)-induced colon cancer in rats, colon tumours were induced using an established protocol and aspirin was given in the diet at 500 p.p.m. during various stages of colon carcinogenesis. Results indicate that only aspirin treatment throughout the entire carcinogenic period significantly reduced tumour incidence and volume whereas intermittent aspirin dosing increased tumour number and/or volume, suggesting that aspirin must be used for an extended period in order to gain any chemopreventive benefit. © 1999 Cancer Research Campaig

Use of tobacco and alcohol by Swiss primary care physicians: a cross-sectional survey

BACKGROUND: Health behaviours among doctors has been suggested to be an important marker of how harmful lifestyle behaviours are perceived. In several countries, decrease in smoking among physicians was spectacular, indicating that the hazard was well known. Historical data have shown that because of their higher socio-economical status physicians take up smoking earlier. When the dangers of smoking become better known, physicians began to give up smoking at a higher rate than the general population. For alcohol consumption, the situation is quite different: prevalence is still very high among physicians and the dangers are not so well perceived. To study the situation in Switzerland, data of a national survey were analysed to determine the prevalence of smoking and alcohol drinking among primary care physicians. METHODS: 2'756 randomly selected practitioners were surveyed to assess subjective mental and physical health and their determinants, including smoking and drinking behaviours. Physicians were categorised as never smokers, current smokers and former smokers, as well as non drinkers, drinkers (AUDIT-C < 4 for women and < 5 for men) and at risk drinkers (higher scores). RESULTS: 1'784 physicians (65%) responded (men 84%, mean age 51 years). Twelve percent were current smokers and 22% former smokers. Sixty six percent were drinkers and 30% at risk drinkers. Only 4% were never smokers and non drinkers. Forty eight percent of current smokers were also at risk drinkers and 16% of at risk drinkers were also current smokers. Smoking and at risk drinking were more frequent among men, middle aged physicians and physicians living alone. When compared to a random sample of the Swiss population, primary care physicians were two to three times less likely to be active smokers (12% vs. 30%), but were more likely to be drinkers (96% vs. 78%), and twice more likely to be at risk drinkers (30% vs. 15%). CONCLUSION: The prevalence of current smokers among Swiss primary care physicians was much lower than in the general population in Switzerland, reflecting that the hazards of smoking are well known to doctors. However, the opposite was found for alcohol use, underlining the importance of making efforts in this area to increase awareness among physicians of the dangers of alcohol consumption