Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia.

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Fosslien E

Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia.

Crit Rev Clin Lab Sci. 2000 Oct;37(5):431-502.

PubMed ID

11078056 [ View in PubMed

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Abstract

Several types of human tumors overexpress cyclooxygenase (COX) -2 but not COX-1, and gene knockout transfection experiments demonstrate a central role of COX-2 in experimental tumorigenesis. COX-2 produces prostaglandins that inhibit apoptosis and stimulate angiogenesis and invasiveness. Selective COX-2 inhibitors reduce prostaglandin synthesis, restore apoptosis, and inhibit cancer cell proliferation. In animal studies they limit carcinogen-induced tumorigenesis. In contrast, aspirin-like nonselective NSAIDs such as sulindac and indomethacin inhibit not only the enzymatic action of the highly inducible, proinflammatory COX-2 but the constitutively expressed, cytoprotective COX-1 as well. Consequently, nonselective NSAIDs can cause platelet dysfunction, gastrointestinal ulceration, and kidney damage. For that reason, selective inhibition of COX-2 to treat neoplastic proliferation is preferable to nonselective inhibition. Selective COX-2 inhibitors, such as meloxicam, celecoxib (SC-58635), and rofecoxib (MK-0966), are NSAIDs that have been modified chemically to preferentially inhibit COX-2 but not COX-1. For instance, meloxicam inhibits the growth of cultured colon cancer cells (HCA-7 and Moser-S) that express COX-2 but has no effect on HCT-116 tumor cells that do not express COX-2. NS-398 induces apoptosis in COX-2 expressing LNCaP prostate cancer cells and, surprisingly, in colon cancer S/KS cells that does not express COX-2. This effect may due to induction of apoptosis through uncoupling of oxidative phosphorylation and down-regulation of Bcl-2, as has been demonstrated for some nonselective NSAIDs, for instance, flurbiprofen. COX-2 mRNA and COX-2 protein is constitutively expressed in the kidney, brain, spinal cord, and ductus deferens, and in the uterus during implantation. In addition, COX-2 is constitutively and dominantly expressed in the pancreatic islet cells. These findings might somewhat limit the use of presently available selective COX-2 inhibitors in cancer prevention but will probably not deter their successful application for the treatment of human cancers.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sulindac	Prostaglandin G/H synthase 2	Protein	Humans	Yes	Inhibitor	Details