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Celecoxib pre-treatment in human colorectal adenocarcinoma patients.

ABSTRACT: Pharmacological inhibition of cyclooxygenase-2 (COX-2) is being explored as a chemotherapeutic option because COX-2 protein expression is often elevated in many cancers. Cancer cells treated with COX-2 inhibitors, such as the selective COX-2 inhibitor celecoxib, show growth inhibition and the induction of apoptosis, through alterations in inflammatory processes, angiogenesis, cell adhesion and transforming growth factor-β signaling. This study was conducted to determine if the same processes are relevant to celecoxib’s effects on human colorectal adenocarcinomas treated in vivo. A cohort of 23 patients with primary colorectal adenocarcinomas was randomized to receive a 7-day course of celecoxib (400 mg b.i.d.) or no drug prior to surgical resection. Gene expression profiling was performed on resected adenocarcinomas from patients with and without celecoxib pre-treatment. Using fold change (>1.5) and p-value (<0.05) cut-offs, 190 genes were differentially expressed between adenocarcinomas from patients receiving celecoxib and those that did not. Of the differentially expressed genes, multiple genes involved in cellular lipid and glutathione metabolism showed decreased expression levels in celecoxib pre-treated samples; changes associated with diminished cellular proliferation. Other observed gene expression changes consistent with reduced proliferation include: altered expression of genes involved in cell adhesion (including collagen, laminin, von Willebrand factor and tenascin C), increased expression of inflammatory modulators (including inerleukin-6, S100 calcium binding protein A8, and several chemokines) and decreased expression of the pro-angiogenic gene, angiogenin. Celecoxib pre-treatment for 7 days in vivo is associated with alterations in colorectal adenocarcinoma gene expression which are suggestive of diminished cellular proliferation. Keywords: treatment outcome

ORGANISM(S): Homo sapiens

PROVIDER: GSE11237 | GEO | 2008/08/21

SECONDARY ACCESSION(S): PRJNA106739

REPOSITORIES: GEO

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Project description:Pharmacological inhibition of cyclooxygenase-2 (COX-2) is being explored as a chemotherapeutic option because COX-2 protein expression is often elevated in many cancers. Cancer cells treated with COX-2 inhibitors, such as the selective COX-2 inhibitor celecoxib, show growth inhibition and the induction of apoptosis, through alterations in inflammatory processes, angiogenesis, cell adhesion and transforming growth factor-Î² signaling. This study was conducted to determine if the same processes are relevant to celecoxibâs effects on human colorectal adenocarcinomas treated in vivo. A cohort of 23 patients with primary colorectal adenocarcinomas was randomized to receive a 7-day course of celecoxib (400 mg b.i.d.) or no drug prior to surgical resection. Gene expression profiling was performed on resected adenocarcinomas from patients with and without celecoxib pre-treatment. Using fold change (>1.5) and p-value (<0.05) cut-offs, 190 genes were differentially expressed between adenocarcinomas from patients receiving celecoxib and those that did not. Of the differentially expressed genes, multiple genes involved in cellular lipid and glutathione metabolism showed decreased expression levels in celecoxib pre-treated samples; changes associated with diminished cellular proliferation. Other observed gene expression changes consistent with reduced proliferation include: altered expression of genes involved in cell adhesion (including collagen, laminin, von Willebrand factor and tenascin C), increased expression of inflammatory modulators (including inerleukin-6, S100 calcium binding protein A8, and several chemokines) and decreased expression of the pro-angiogenic gene, angiogenin. Celecoxib pre-treatment for 7 days in vivo is associated with alterations in colorectal adenocarcinoma gene expression which are suggestive of diminished cellular proliferation. Experiment Overall Design: Patients undergoing surgical resection of histologically proven primary colorectal adenocarcinomas were consented for participation in the study. The patients enrolled in this study were randomized to receive either 400 mg celecoxib two times per day (n=11) or no COX-2 inhibitor (n=12) for 7 days prior to surgical resection. Total RNA (5 ug) from each sample was converted to double stranded cDNA using a dT-T7 promoter primer. The double stranded cDNA was then used as a template to synthesize biotinylated RNA, which was fragmented and hybridized to the Affymetrix HG_U95av2 microarray chip using Affymetrixâs labeling and hybridization protocol. Experiment Overall Design: The array data was imported into GeneSpring GX 7.3 using the GC-RMA file preprocessor. The data was normalized by: (1) setting all expression measurements <0.01 to 0.01, (2) a per chip normalization to the 50th percentile, and (3) a per gene normalization to the median value across all chips.

Project description:Cyclooxygenase-2 (COX-2) is upregulated in pancreatic ductal adenocarcinomas (PDAC). However, how COX-2 promotes PDAC development is unclear. While previous studies have evaluated the efficacy of COX-2 inhibition via the use of non steroidal anti-inflammatory drugs (NSAIDs) or the COX-2 inhibitor celecoxib in PDAC models, none have addressed the cell intrinsic vs. microenvironment roles of COX-2 in modulating PDAC initiation and progression. We tested the cell intrinsic role of COX-2 in PDAC progression, using both loss-of-function and gain-of-function approaches. Cox-2 deletion in Pdx1+ pancreatic progenitor cells significantly delays the development of PDAC in mice with K-ras activation and Pten haploinsufficiency. Conversely, COX-2 over-expression promotes early onset and progression of PDAC in the K-ras mouse model. Loss of PTEN function is a critical factor in determining lethal PDAC onset and overall survival. Mechanistically, COX-2 over-expression increases P-AKT levels in the precursor lesions of Pdx1+;K-rasG12D/+;Ptenlox/+ mice in the absence of Pten LOH. In contrast, Cox-2 deletion in the same setting diminishes P-AKT levels and delays cancer progression. These data suggest an important cell intrinsic role for COX-2 in tumor initiation and progression through activation of the PI3K/AKT pathway. PDAC that is independent of intrinsic COX-2 expression eventually develops with decreased FKBP5 and increased GRP78 expression, two alternate pathways leading to AKT activation. Together, these results support a cell intrinsic role for COX-2 in PDAC development and suggest that, while anti-COX-2 therapy may delay the development and progression of PDAC, mechanisms known to increase chemoresistance through AKT activation must also be overcome. Murine mutants with pancreatic specific loss of Pten (Pten +/-) and K-ras activation (K-rasG12D) and either COX-2 over-expression (Cox-2 COE) or knockout (Cox-2 KO) under regulation of the Pdx-1 promoter developed pancreatic ductal adenocarcinoma. RNA was extracted from pancreatic tumors from individual mutants with pathology thought to closely mimic the human disease. Pancreatic tissue was subject to RNA extraction and hybridization on Affymetrix cDNA microarrays.

Project description:Cyclooxygenase (COX) inhibition is of concern in fish because COX inhibitors (e.g., ibuprofen) are ubiquitous in aquatic systems/fish tissues, and can disrupt synthesis of prostaglandins that modulate a variety of essential biological functions including reproduction. Transcriptomic data and publicly available high throughput toxicity data were utilized to develop putative adverse outcome pathways (AOPs) for molecular initiating event (MIE) of COX inhibition. Effects of a waterborne exposure to indomethacin (IN; 100 Âµg/L), ibuprofen (IB; 200 Âµg/L) and celecoxib (CX; 20 Âµg/L) on liver metabolome and ovarian gene expression (using oligonucleotide microarrays) in sexually mature fathead minnows were examined. Metabolomic profiles of IN, IB and CX were not significantly different from control or one another. Exposure to IB and CX resulted in differential expression of comparable numbers of genes (IB = 433, CX= 545). In contrast, 2558 genes were differentially expressed in IN-treated fish. Functional analyses (canonical pathway and gene set enrichment) indicated extensive effects of IN on prostaglandin synthesis pathway, oocyte meiosis and several other processes consistent with physiological roles of prostaglandins. Transcriptomic data was congruent with apical endpoint data - IN reduced plasma prostaglandin F2 alpha concentrations, and ovarian COX activity, whereas IB and CX did not. Putative AOPs pathways for COX inhibition (MIE) leading to reproductive failure (adverse outcome) via reduction of: 1) ovulation, 2) reproductive behaviors mediated by exogenous and endogenous prostaglandins, and 3) oocyte maturation were developed. Adult fathead minnow were exposed to either 100 Âµg/L indomethacin, 200 Âµg/L ibuprofen, 20 Âµg/L celecoxib or UV-treated Lake Superior (control) water for 96 hours. After exposure, microarray analyses were conducted using the female gonads (n=7-8 per treatment) and metabolomic analyses were conducted using the livers of all the exposed fish.

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Celecoxib pre-treatment in human colorectal adenocarcinoma patients.

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