Celecoxib for the Prevention of Colorectal Adenomas: Results of a Suspended Randomized Controlled Trial

Thompson, Patricia A.; Ashbeck, Erin L.; Roe, Denise J.; Fales, Liane; Buckmeier, Julie A.; Wang, Fang; Bhattacharyya, Achyut; Hsu, Chiu Hsieh; Chow, Sherry; Ahnen, Dennis J.; Boland, C. Richard; Heigh, Russell I.; Fay, David E.; Hamilton, Stanley R.; Jacobs, Elizabeth T.; Martínez, Elena; Alberts, David S.; Lance, Peter

doi:10.1093/jnci/djw151

Cited by 53 publications

(50 citation statements)

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“…There are concerns regarding the cardiotoxicity of several agents used both in cancer treatment and in cancer prevention [ 46 ], among which the case of celecoxib is paradigmatic [ 9 , 10 ]. In addition to the previously discussed formation of bulky DNA adducts in the heart of mice treated with celecoxib, it was of interest to evaluate modulation by this drug of those miRNAs that are known to target the heart.…”

Section: Discussionmentioning

confidence: 99%

“…Upper GI complication rates in clinical trials have been reported to be significantly lower for celecoxib than for traditional nonselective NSAIDs [ 6 – 8 ]. While several coxibs have been withdrawn from the market due to safety concerns, and especially to cardiovascular adverse events [ 9 , 10 ], celecoxib continues to be available for use in many countries [ 11 ]. This coxib is approved by the US Food and Drug Administration (FDA) ( https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm240959.htm ).…”

Section: Introductionmentioning

confidence: 99%

“…It has been shown that COX-2 downregulation inhibits colorectal carcinogenesis [ 10 ]. Moreover, based on reports that suggest an association between cigarette smoke (CS) and COX-2-associated risk to develop cancer, celecoxib is under scrutiny for its possible ability to prevent cancer and for antagonizing the carcinogenic properties of CS, the most important threat to human health.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of genomic and epigenetic end-points by celecoxib

et al. 2018

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Celecoxib, a nonsteroidal anti-inflammatory drug that selectively targets cyclooxygenase-2, is a promising cancer chemopreventive agent. However, safety concerns have been raised in clinical trials evaluating its ability to prevent colorectal adenomas. The rationale for the herein reported studies was to analyze genomic and epigenetic end-points aimed at investigating both the chemopreventive properties of celecoxib towards cigarette smoke-associated molecular alterations and its possible adverse effects. We carried out three consecutive studies in mice treated with either smoke and/or celecoxib. Study 1 investigated early DNA alterations (DNA adducts, oxidative DNA damage, and systemic genotoxic damage) and epigenetic alterations (expression of 1,135 microRNAs) in lung and blood of Swiss H mice; Study 2 evaluated the formation of DNA adducts in lung, liver, and heart; and Study 3 evaluated the expression of microRNAs in 10 organs and 3 body fluids of ICR (CD-1) mice. Surprisingly, the oral administration of celecoxib to smoke-free mice resulted in the formation of DNA adducts in both lung and heart and in dysregulation of microRNAs in mouse organs and body fluids. On the other hand, celecoxib attenuated smoke-related DNA damage and dysregulation of microRNA expression. In conclusion, celecoxib showed pleiotropic properties and multiple mechanisms by counteracting the molecular damage produced by smoke in a variety of organs and body fluids. However, administration of celecoxib to non-smoking mice resulted in evident molecular alterations, also including DNA and RNA alterations in the heart, which may bear relevance in the pathogenesis of the cardiovascular adverse effects of this drug.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulation of genomic and epigenetic end-points by celecoxib

et al. 2018

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“…It is important to diagnose and have suitable treatments for IBD not only because it has not ignorable effect on daily life but also it has a big risk for colorectal cancer. COX-2 is lightening up with his potential for promising target to treatment options for colorectal cancer [17,18]. COX-2 and IBD are underlined the colorectal cancer in somehow with their unclear role on the pathway.…”

Section: Discussionmentioning

confidence: 99%

The role of COX-2 gene variants on the disease mechanism of inflammatory bowel disease in a Turkish population

İplik

Kahraman

Ertuğrul³

et al. 2018

Archives of Clinical and Experimental Medicine

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Aim: Inflammatory bowel disease has two major types: Crohn's disease and ulcerative colitis that occur in the gastrointestinal tract with unknown etiology. COX-2 has important role on carcinogenesis process including colon cancer supporting the tumor growth. COX-2 was also known due to its ability to change homeostasis on colonic mucosa in inflammatory cells on patients who have inflammatory bowel disease. In this study, we have aimed to find a linkage between inflammatory bowel disease and COX-2 in a Turkish population. Methods:A total of 106 patients,42 with Crohn's disease and 64 with ulcerative colitis and 121 healthy control subjects were included the study. Gene variants of COX-2-765G→C and COX-2-1195A→G were analyzed by polymerase chain reaction and restriction fragment length polymorphism techniques. Results: The results demonstrated that COX-2-1195A→G gene variants AA carriers were statistically found in high level on patients with both ulcerative colitis (p=0.001) and Crohn's disease (p=0.008). In contrast, AG genotype and G carriers were statistically found higher in control group (Crohn's disease, p=0.005 for AG and p= 0.008 for G; ulcerative colitis, p=0.001 for AG and p=0.001 for G). Conclusion: In this research, we have observed important and questionable results between inflammatory bowel disease and COX-2, especially COX-2-1195A→G gene variants AA carriers in a Turkish population. Researches need to focus on their local roles on inflammatory bowel disease pathogenesis with large sample size.

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“…In summary, COX-2 promotes carcinogenesis and cancer progression through participating in promoting cell proliferation, inhibiting cell apoptosis, enhancing angiogenesis, promoting cancer stem cell formation, and facilitating immune response shift in tumor microenvironment, COX-2 is deemed to be a promising molecular target for CRC treatment. One randomized controlled trial has shown that COX-2 inhibitor celecoxib prevents the occurrence of colonic adenoma, which is a precancerous condition of CRC [ 18 ]. A meta-analysis also shows that aspirin (a nonselective COX inhibitor) improves CRC patients survival especially in CRC patients with high COX-2 expression in tumor issues [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers

Zhang

Zheng

et al. 2017

PLoS ONE

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Cyclooxygenase (COX) is the rate-limiting enzyme in prostaglandins (PGs) biosynthesis. Previous studies indicate that COX-2, one of the isoforms of COX, is highly expressed in colon cancers and plays a key role in colon cancer carcinogenesis. Thus, searching for novel transcription factors regulating COX-2 expression will facilitate drug development for colon cancer. In this study, we identified XRCC5 as a binding protein of the COX-2 gene promoter in colon cancer cells with streptavidin-agarose pulldown assay and mass spectrometry analysis, and found that XRCC5 promoted colon cancer growth through modulation of COX-2 signaling. Knockdown of XRCC5 by siRNAs inhibited the growth of colon cancer cells in vitro and of tumor xenografts in a mouse model in vivo by suppressing COX-2 promoter activity and COX-2 protein expression. Conversely, overexpression of XRCC5 promoted the growth of colon cancer cells by activating COX-2 promoter and increasing COX-2 protein expression. Moreover, the role of p300 (a transcription co-activator) in acetylating XRCC5 to co-regulate COX-2 expression was also evaluated. Immunofluorescence assay and confocal microscopy showed that XRCC5 and p300 proteins were co-located in the nucleus of colon cancer cells. Co-immunoprecipitation assay also proved the interaction between XRCC5 and p300 in nuclear proteins of colon cancer cells. Cell viability assay indicated that the overexpression of wild-type p300, but not its histone acetyltransferase (HAT) domain deletion mutant, increased XRCC5 acetylation, thereby up-regulated COX-2 expression and promoted the growth of colon cancer cells. In contrast, suppression of p300 by a p300 HAT-specific inhibitor (C646) inhibited colon cancer cell growth by suppressing COX-2 expression. Taken together, our results demonstrated that XRCC5 promoted colon cancer growth by cooperating with p300 to regulate COX-2 expression, and suggested that the XRCC5/p300/COX-2 signaling pathway was a potential target in the treatment of colon cancers.

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Celecoxib for the Prevention of Colorectal Adenomas: Results of a Suspended Randomized Controlled Trial

Abstract: Limited-duration celecoxib prevents adenoma recurrence in patients with prior high-risk adenomas, in whom strategies to minimize cardiovascular toxicity might be feasible.

Cited by 53 publications

References 29 publications

Modulation of genomic and epigenetic end-points by celecoxib

Modulation of genomic and epigenetic end-points by celecoxib

The role of COX-2 gene variants on the disease mechanism of inflammatory bowel disease in a Turkish population

XRCC5 cooperates with p300 to promote cyclooxygenase-2 expression and tumor growth in colon cancers

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