Non-Steroidal Anti-Inflammatory Drug Use and Colorectal Polyps in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Department of Biostatistics and Research Epidemiology, Josephine Ford Cancer Center, Henry Ford Hospital, Detroit, Michigan 48202, USA.
The American Journal of Gastroenterology (Impact Factor: 10.76). 12/2010; 105(12):2646-55. DOI: 10.1038/ajg.2010.349
Source: PubMed


Non-steroidal anti-inflammatory drugs (NSAIDs) have been documented in animal and human studies to reduce risk for colorectal cancer and adenomatous polyps, but risk modification for subgroups of the population and effects on hyperplastic polyps have been less studied.
Data on recent use of two frequently ingested NSAIDs, aspirin and ibuprofen, were collected at baseline from participants aged 55-74 years in the 10 centers of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants randomized to the intervention arm of the trial received a flexible sigmoidoscopy during a baseline examination. Follow-up of detected polyps was accomplished outside the Trial setting and relevant records were sought and abstracted. Cases (n=4,017) included subjects with a biopsy-proven polyp in the left side of the colon (descending colon, sigmoid, and rectum) detected as a consequence of PLCO screening; controls (n=38,396) were subjects with no left-sided colon polyp.
Regular use of aspirin (≥ 4 times/month) in the past year was inversely associated with hyperplastic polyps (odds ratios (OR)=0.8, 95% confidence interval (CI)=0.7-0.9), adenomatous polyps (OR=0.8, 95% CI=0.8-0.9), and advanced adenomas (OR=0.8, 95% CI=0.7-0.9). As frequency of aspirin use increased, the prevalence of polyps decreased significantly for each histological classification (P for trend ≤ 0.0004). Similar patterns were found for adenomas and ibuprofen. Overall protection was consistent in both the descending colon or sigmoid and the rectum, but more evident in males. In males, the OR for heavy use of combined aspirin and ibuprofen (≥ 2 times/day) was 0.6 (95% CI=0.5-0.8), as opposed to 0.9 (95% CI=0.8-1.1) in females. The protective effects of NSAIDs for females were apparent only among those with body mass index (BMI) <25 (OR=0.8, 95% CI=0.7-1.0 for regular use of NSAIDs; P interaction=0.04). We also found a slightly stronger protection of NSAIDs in the 70-74 years age group compared with those aged 55-69 years.
This study of a large general risk population supports previous work that recent use of aspirin and ibuprofen is associated with a decreased risk of colorectal adenomas and demonstrates that this protective effect may be stronger in certain population subgroups and is also evident for aspirin and hyperplastic polyps.

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    • "Chronic inflammation has been proposed as a risk factor for ovarian cancer 3, 4. Aspirin (acetylsalicylate) is one of the most commonly used nonsteroidal anti-inflammatory drugs in the United States 5, and its use has increased significantly over the last 5 years 6. Although the accumulated evidence shows that aspirin use is associated with a reduced risk of prostate 7, 8, breast 9, colorectal 9, 10 and endometrial cancer 11, the relationship between aspirin and ovarian cancer risk remains controversial. Some investigators have found no association 9, 12-14 while others reported an inverse association between the use of aspirin and ovarian cancer 15-17. "
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    ABSTRACT: Objective: Although aspirin has been associated with a reduction of the risk of cancer when used as a nonsteroidal anti-inflammatory drug, its use to reduce the risk of ovarian cancer is controversial. Ovarian cancer cells usually express high levels of cyclooxygenase-1 (COX)-1. Because aspirin is a rather selective inhibitor of COX-1, the ability of aspirin to reduce the risk of ovarian cancer may be dependent on the level of COX-1 expression in those cells. Furthermore, epidermal growth factor receptor (EGFR) is frequently overexpressed in the malignant phenotype of ovarian cancer leading to increased cell proliferation and survival. Here we investigated if aspirin attenuates EGFR-activated ovarian cancer cell growth in a COX-1 dependent manner. Methods: Cell viability assays and Western blot analyses were used to determine the effect of aspirin on EGF-stimulated cell proliferation. Gene silencing and gene expression techniques were employed to knockdown or to express COX-1, respectively. Results: Aspirin inhibited cell viability induced by EGF in a dose dependent manner in COX-1 positive ovarian cancer cells. On the other hand, aspirin had no effect on cell viability in COX-1 negative ovarian cancer cells. In particular, aspirin decreased phosphorylated Akt and Erk activated by EGF. COX-1 silencing in COX-1 positive cells attenuated the inhibitory effect of aspirin on EGF-stimulated cell viability. Furthermore, we developed a COX-1 expressing cell line (SKCOX-1) by stably transfecting COX-1 expression vector into COX-1 negative SKOV-3 cells. SKCOX-1 cells were more responsive to aspirin when compared to cells transfected with empty vector, and decreased EGF-activated Akt and Erk as well as cell viability. Conclusions: Taken together, aspirin inhibits viability of ovarian cancer cells by blocking phosphorylation of Akt and Erk activated by EGF. Thus it may potentiate the therapeutic efficacy of drugs used to treat COX-1 positive ovarian cancer subsets.
    Full-text · Article · Sep 2013 · Journal of Cancer
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    • "The overexpression of PMPMEase in colorectal cancer, its inhibition by curcumin and its differential susceptibility to the PUFAs and PGs are significant against the backdrop of COX-2 overexpression especially in colorectal cancer. Furthermore, long-term use of NSAIDs is associated with lower cancer risks [78, 79]. Considering this and the numerous reports that COX-2 and PGs are important in the development and progression of cancers [80], it has been opined that COX-2-selective inhibition holds a promising role in cancer chemoprevention [78]. "
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    ABSTRACT: Inhibition of PMPMEase, a key enzyme in the polyisoprenylation pathway, induces cancer cell death. In this study, purified PMPMEase was inhibited by the chemopreventive agent, curcumin, with a K i of 0.3 μ M (IC50 = 12.4 μ M). Preincubation of PMPMEase with 1 mM curcumin followed by gel-filtration chromatography resulted in recovery of the enzyme activity, indicative of reversible inhibition. Kinetics analysis with N-para-nitrobenzoyl-S-trans,trans-farnesylcysteine methyl ester substrate yielded K M values of 23.6 ± 2.7 and 85.3 ± 15.3 μ M in the absence or presence of 20 μ M curcumin, respectively. Treatment of colorectal cancer (Caco2) cells with curcumin resulted in concentration-dependent cell death with an EC50 of 22.0 μ g/mL. PMPMEase activity in the curcumin-treated cell lysate followed a similar concentration-dependent profile with IC50 of 22.6 μ g/mL. In colorectal cancer tissue microarray studies, PMPMEase immunoreactivity was significantly higher in 88.6% of cases compared to normal colon tissues (P < 0.0001). The mean scores ± SEM were 91.7 ± 11.4 (normal), 75.0 ± 14.4 (normal adjacent), 294.8 ± 7.8 (adenocarcinoma), and 310.0 ± 22.6 (mucinous adenocarcinoma), respectively. PMPMEase overexpression in colorectal cancer and cancer cell death stemming from its inhibition is an indication of its possible role in cancer progression and a target for chemopreventive agents.
    Full-text · Article · Jul 2013
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    • "Although multiple medicinal applications of longan flowers are recorded in TCM pharmacopoeia, the scientific evidence related to their effect on human health has been accumulating over recent years. We have demonstrated that the hot water reflux or ethanol extract of the longan flower, contained abundant proantocyanidins and rarely anthocyanins, suppresses nitric oxide and prostaglandin E2 production in lipopolysaccharide -stimulated macrophage cell line RAW264.7 and may be the potential source of natural dietary anti-oxidants and antiinflammatory agent[20]. The longan flower extract (LFE), analyzed by Professor Hwang and colleagues, exhibits a strong anti-oxidant activity, which is mainly due to (-)epicatechin and proanthocyanidin A2[26]. "
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    ABSTRACT: Polyphenol-rich plants are known to possess benefits to human health. Recent studies have revealed that many Traditional Chinese Medicines (TCMs) are rich sources of polyphenols and exhibit antioxidant and anti-inflammatory activities, and these TCMs have been shown experimentally to overcome some chronic diseases, including cancer. Longan flowers and seeds, two TCMs traditionally used for relieving pain and urinary diseases, have been revealed in our recent reports and other studies to possess rich amounts of polyphenolic species and exhibit strong anti-oxidant activity, and these could be applied for the treatment of diabetes and cancer. Herein, we review the recent findings regarding the benefits of these two TCMs in the treatment of human cancer and the possible cellular and molecular mechanisms of both substances.
    Preview · Article · Aug 2012
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