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Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2

Abstract

Population-based studies have established that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), reduces the relative risk for developing colorectal cancer. These studies led to the identification of a molecular target, COX-2, that is involved in tumour promotion during colorectal cancer progression. Recent studies in humans indicate that therapy with specific COX-2 inhibitors might be an effective approach to colorectal cancer prevention and treatment.

Key Points

  • Population-based studies have established that chronic intake of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) reduces the relative risk for developing colorectal cancer. In randomized clinical trials, administration of a NSAID reduces intestinal polyp burden in patients with familial adenomatous polyposis (FAP).

  • Traditional NSAIDs inhibit the activity of cyclooxygenases 1 and 2 (COX-1 and COX-2), enzymes that catalyse the rate-limiting step in the conversion of arachidonate to prostanoids. Selective COX-2 inhibitors have now been developed and these compounds retain the anti-inflammatory activity, but cause fewer gastrointestinal side effects, than non-selective NSAIDs.

  • In rodent models of intestinal neoplasia, both non-selective and COX-2-selective NSAIDs are potent suppressors of colorectal cancer cell growth.

  • The anti-tumour activity of NSAIDs has been attributed to both COX-dependent and COX-independent mechanisms. The non-COX effects are probably relevant when high doses of NSAIDs are used and may involve inhibition of the NF-κB pathway, the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors, or direct actions on certain components of the apoptotic machinery.

  • The most direct evidence implicating a pro-oncogenic function for COX-2 has come from genetic studies in mice. For example, ApcΔ716 mice (a model of FAP) have an 86% reduction in polyp number in a Cox-2−/− background compared with control animals.

  • The expression of COX-2, but not COX-1, is elevated in many colorectal cancers and the protein has been localized to both stromal and epithelial compartments. At least one mechanism by which elevated COX-2 promotes carcinogenesis is through stimulation of tumour-associated angiogenesis.

  • Limited work has been done to identify the specific prostaglandin (PG) subtypes and receptors downstream of COX-2 that are involved in colorectal cancer progression. Some experiments have indicated that PGE2 can promote colorectal cancer growth, in part through activation of the PGE2 receptor subtype EP1.

  • Recently, selective COX-2 inhibitors were shown to reduce polyp burden in individuals with FAP. Ongoing clinical trials are examining the ability of COX-2 inhibitors, alone or in combination with other therapeutic agents, to either prevent polyp formation or treat existing colorectal tumours in the general population.

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Figure 1: COX enzymes in prostaglandin synthesis.
Figure 2: Non-COX targets of NSAIDs.
Figure 3: Mechanisms by which elevated COX-2 promotes colorectal cancer growth.
Figure 4: Prostaglandin signal-transduction pathways.

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Acknowledgements

Our work is supported in part from United States Public Health Services Grants. R.N.D is a recipient of a VA (Veterans Affairs) Research Merit Grant and is the Mina C. Wallace Professor of Cancer Prevention. We also thank the T.J. Martell Foundation and the NCCRA (National Colorectal Cancer Research Alliance) for generous support.

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Correspondence to Raymond N. DuBois.

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bladder cancer

breast cancer

gallbladder cancer

gastric cancer

oesophageal cancer

ovarian cancer

pancreatic cancer

prostate cancer

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APC

BAX

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COX-1

Cox1

Cox2

cyclooxygenase-2

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PPARα

PPARδ

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celecoxib

indomethacin

rofecoxib

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Glossary

PROSTAGLANDINS

Any of a class of hormone-like, lipid-soluble regulatory molecules constructed from polyunsaturated fatty acids such as arachidonate. These molecules participate in diverse body functions, such as smooth muscle contraction and relaxation, vasodilation and regulation of kidney function.

ARACHADONIC ACID

A 20-carbon polyunsaturated fatty acid usually found esterified in membrane glycerophosophlipids at the sn-2 position. The phospholipase A2 (PLA2) family of enzymes catalyse the release of arachidonic acid from the membrane in response to various stimuli. The lipoxygenase and cyclooxygenase enzymes use liberated arachadonic acid as a substrate to generate eicosanoids.

AUTOCRINE

A form of bioregulation in which a secretory factor affects only the cell from which it was secreted.

PARACRINE

A form of bioregulation in which a secretion produced by one cell type in a tissue diffuses through the tissue and affects another cell type in the same tissue.

PHORBOL ESTERS

Polycyclic compounds isolated from croton oil that are potent co-carcinogens or tumour promoters. They are diacylglycerol analogues and irreversibly activate protein kinase C.

MURINE MAMMARY TUMOUR VIRUS (MMTV) PROMOTER/ENHANCER

MMTV causes mammary adenocarcinoma in infected mice and selectively replicates in the alveolar epithelial cells of the mammary gland. The MMTV promoter/enhancer has often been used to direct the expression of transgenes specifically in the mammary gland.

NF-κB

A transcription factor involved in regulating the expression of inflammatory and growth- control genes in several cells and tissues. Various stimuli (for example, tumour necrosis factor, phorbol esters and bacterial lipopolysaccharide) allow NF-κB to enter the nucleus and bind to regulatory elements of target genes.

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS)

A family (subtypes α, δ and γ) of ligand-activated transcription factors that are members of the nuclear-hormone-receptor superfamily. PPARs have important functions in fatty-acid catabolism and storage, and endogenous PPAR ligands include fatty acids and certain fatty acid metabolites.

MATRIX METALLOPROTEINASES

A family of proteolytic enzymes that degrade the extracellular matrix and have important roles in tissue remodelling and tumour metastasis.

PI3K/AKT PATHWAY

The phosphatidylinositol 3- kinase (PI3K) family of enzymes are activated in response to a wide variety of stimuli and catalyse the phophorylation of inositol lipds at the D-3 position of the inositol ring. These phosphoinositides act as second messengers; a primary target is the serine/threonine kinase AKT (protein kinase B). Activated AKT phosphorylates several cellular targets, including proteins involved in cell survival, proliferation and migration.

HEREGULIN-β1

The ERBB/HER family of growth factor receptors have vital roles in the morphogenesis and maintenance of epithelial organs. heregulin-β1 is a ligand for ERBB/HER receptor subtypes ERBB3/HER-3 and ERBB4/HER-4.

IMMEDIATE EARLY GENES

A category of genes that represent the first transcriptional response of a cell to certain stimuli (for example, growth factors). These genes are generally induced within 15 minutes of stimulation, and the induction does not require de novo protein synthesis.

PROCTOCOLECTOMY

A surgical procedure that involves the excision of the colon and rectum followed by the formation of an ileoanal reservoir (pouch).

CHROMOSOMAL INSTABILITY (CIN)

Describes aneuploid tumours in which whole chromosomes or large segments of chromsomes are gained and lost.

MICROSATELLITE INSTABILITY (MIN)

Describes diploid tumours in which genetic instability is due to a high mutation rate, primarily in short nucleotide repeats. Cancers with the MIN phenotype are associated with defects in DNA mismatch- repair genes.

INFLAMMATORY BOWEL DISEASE (IBD)

A general term that refers to chronic inflammatory disorders of the intestine, such as Crohn's disease and ulcerative colitis. The inflammation causes ulceration of the intestinal lining leading to rectal bleeding, diarrhoea and abdominal pain, and increases the risk of intestinal cancer. IBD is an autoimmune disease and is thought to have a significant genetic component.

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Gupta, R., DuBois, R. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1, 11–21 (2001). https://doi.org/10.1038/35094017

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