Celecoxib treatment alters the gene expression profile of normal colonic mucosa

University of Toronto, Toronto, Ontario, Canada
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 07/2006; 15(7):1382-91. DOI: 10.1158/1055-9965.EPI-04-0866
Source: PubMed


A clinical trial was recently conducted to evaluate the safety and efficacy of a selective inhibitor of cyclooxygenase-2 (celecoxib) in hereditary nonpolyposis colon cancer patients. In a randomized, placebo-controlled phase I/II multicenter trial, hereditary nonpolyposis colon cancer patients and gene carriers received either celecoxib at one of two doses or placebo. The goal was to evaluate the effects of these treatment arms on a number of endoscopic and tissue-based biomarker end points after 12 months of treatment. As part of this trial, we analyzed gene expression by cDNA array technology in normal descending (rectal) colonic mucosa of patients before and after treatment with celecoxib or placebo. We found that treatment of patients with celecoxib at recommended clinical doses (200 and 400 mg p.o. bid), in contrast to treatment with placebo, leads to changes in expression of >1,400 genes in the healthy colon, although in general, the magnitude of changes is <2-fold. Twenty-three of 25 pairs of colon biopsies taken before and after celecoxib treatment can be classified correctly by the pattern of gene expression in a leave-one-out cross-validation. Immune response, particularly T- and B-lymphocyte activation and early steps of inflammatory reaction, cell signaling and cell adhesion, response to stress, transforming growth factor-beta signaling, and regulation of apoptosis, are the main biological processes targeted by celecoxib as shown by overrepresentation analysis of the distribution of celecoxib-affected genes across Gene Ontology categories. Analysis of possible cumulative effects of celecoxib-induced changes in gene expression indicates that in healthy colon, celecoxib may suppress the immune response and early steps of inflammation, inhibit formation of focal contacts, and stimulate transforming growth factor-beta signaling.

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    • "Nonconventional chemotherapeutic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and resistant starch have been studied as potential treatments in patients with Lynch syndrome (Burn et al., 2011a;2008;Mathers et al., 2012). COX-2 inhibitors may be efficacious in the treatment of Lynch syndrome as cyclooxygenase-2 (COX-2) is overexpressed in a variety of malignancies, and COX-2 inhibitors have been found to have a protective role against colorectal cancer (Dannenberg and Subbaramaiah, 2003;Glebov et al., 2006;Gupta and Dubois, 2001). Treatment with celecoxib caused complete resolution of adenomatous polyps in 5 of 6 patients with Lynch syndrome but was associated with cardiac side effects such as arrhythmia and angina pectoris (Sheng et al., 2006). "
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    • "In animal models for IBD, direct inhibition of SMAD7 via application of antisense oligonucleotides in vivo resulted in lower production of inflammatory cytokines and less injury to intestinal tissues (Monteleone et al., 2008). Gene expression studies have observed SMAD7 underexpression in colonic mucosa following treatment with COX2 inhibitors (Glebov et al., 2006), and expression of members of the TGFB superfamily, including NSAID-activated gene 1/growth differentiation factor 15 (NAG1/GDF15), is known to be influenced by COX2 (Iguchi et al., 2009). The molecular mechanisms by which antiinflammatory medications would interact directly with SMAD7, specifically, are not yet apparent, and the ability of COX2 overexpression to alter TGFB functionality may very well take place through SMAD-independent pathways (Enders, 2007). "
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