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The structure of NS-398 bound to cyclooxygenase-2.

ABSTRACT: The cyclooxygenases (COX-1 and COX-2) are membrane-associated, heme-containing homodimers that generate prostaglandin H(2) from arachidonic acid (AA) in the committed step of prostaglandin biogenesis and are the targets for nonsteroidal anti-inflammatory drugs (NSAIDs). N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) was the first in a series of isoform-selective drugs designed to preferentially inhibit COX-2, with the aim of ameliorating many of the toxic gastrointestinal side effects caused by conventional NSAID inhibition. We determined the X-ray crystal structure of murine COX-2 in complex with NS-398 utilizing synchrotron radiation to 3.0A resolution. NS-398 binds in the cyclooxygenase channel in a conformation that is different than that observed for other COX-2-selective inhibitors, such as celecoxib, with no discernible penetration into the side pocket formed in COX-2 by the isoform-specific substitutions of I434V, H513R, and I523V. Instead, the methanesulfonamide moiety of NS-398 interacts with the side chain of Arg-120 at the opening of the cyclooxygenase channel, similar to that observed for acidic, nonselective NSAIDs such as indomethacin and flurbiprofen. Our structure validates inhibitor studies that identified Arg-120 as a molecular determinant for time-dependent inhibition of COX-2 by NS-398.

SUBMITTER: Vecchio AJ

PROVIDER: S-EPMC3185125 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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The structure of NS-398 bound to cyclooxygenase-2.

Vecchio Alex J AJ Malkowski Michael G MG

Journal of structural biology 20110806 2

The cyclooxygenases (COX-1 and COX-2) are membrane-associated, heme-containing homodimers that generate prostaglandin H(2) from arachidonic acid (AA) in the committed step of prostaglandin biogenesis and are the targets for nonsteroidal anti-inflammatory drugs (NSAIDs). N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) was the first in a series of isoform-selective drugs designed to preferentially inhibit COX-2, with the aim of ameliorating many of the toxic gastrointestinal side eff ...[more]

PMID: 21843643

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Project description:Cyclooxygenase-2 (COX-2) is an inducible enzyme involved in the conversion of arachadonic acid to prostaglandins and other eicosaniods. Persistent COX-2 expression is associated with multiple forms of cancer.Therefore, there is much interest in COX-2 specific, non-steroidal anti-inflammatory drug use for cancer chemotherapy. The mechanism by which these drugs inhibit tumor growth and progression is unclear, and our knowledge about their potential to prevent or treat prostate cancer is inadequate.The effects of NS-398, a selective COX-2 inhibitor, on human prostate carcinoma cell line LNCaP and the LNCaP subline C4-2b were investigated in this study. NS-398 effects on apoptosis were examined by caspase-3 activity increase, as well as internucleosomal cleavage. ELISA and PCR were used to determine inhibitor effects on macrophage migration inhibitory factor (MIF) and COX-2 production.At 10 microM, NS-398 treatment resulted in increased production of COX-2 and the pro-inflammatory cytokine, MIF by the C4-2b LNCaP subline. NS-398 (10 microM) induces apoptosis in LNCaP cells, but not in the more aggressive, androgen-unresponsive C4-2b cells. The C4-2b cells were observed to continue to proliferate when treated with NS-398 and continued to retain malignant phenotype characteristics. NS-398 treatment resulted in C4-2b cell differentiation into an unusual neuroendocrine-like cell. These neuroendocrine-like cells produced both epithelial (cytokeratin 18 and prostate specific antigen) and neuronal (neuron-specific enolase and chromogranin A) proteins. Furthermore, this C4-2b cellular response to NS-398 was mediated by NF-kappa beta transcription factor activation.These data suggest that COX-2 inhibition induces NF-kappa beta transcription factor activation, which subsequently induces pro-inflammatory protein expression (COX-2 and MIF) and neuroendocrine differentiation in the LNCaP C4-2b subline. These data provide further evidence that pro-inflammatory protein expression may play an important role in prostate cancer progression.

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The structure of NS-398 bound to cyclooxygenase-2.

Publications

The structure of NS-398 bound to cyclooxygenase-2.

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