A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors

Walker, Mark C.; Kurumbail, Ravi G.; Kiefer, James R.; Moreland, Kirby T.; Koboldt, Carol M.; Isakson, Peter C.; Seibert, Karen; Gierse, James K.

doi:10.1042/0264-6021:3570709

Cited by 56 publications

(58 citation statements)

References 40 publications

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“…S1). We also confirmed that, unlike the situation with COX-2, celecoxib is a freely reversible, competitive inhibitor of COX-1 (24). The fact that celecoxib is a freely reversible inhibitor of COX-1 suggests that celecoxib must bind to both monomers of COX-1 to cause enzyme inhibition (10).…”

Section: Resultssupporting

confidence: 65%

“…Inhibition of COX-2 by many nsNSAIDs and by coxibs including celecoxib has at least two phases. The first is a very rapid, second-order kinetic interaction, and this is followed by a much slower, firstorder conformational rearrangement (9,(21)(22)(23)(24). The intrinsic binding affinity of inhibitors for COXs can be estimated by measuring "instantaneous" inhibition that occurs when enzyme, substrate, and inhibitor are mixed without preincubating the inhibitor and enzyme (22).…”

Section: Resultsmentioning

confidence: 99%

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Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

Rimon

Sidhu

Lauver

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

169

210

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Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A 2 formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.arachidonic acid | adrenic acid | nonsteroidal antiinflammatory drugs | platelet | prostaglandin

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

Rimon

Sidhu

Lauver

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

169

210

View full text Add to dashboard Cite

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“…Why this was observed is not certain. It is known that the mechanism by which vitamin D and celecoxib influence PGE2 production is different, the former limiting the production of COX2 (2) and the latter directly inhibiting COX2 (5). If validated, our findings suggest that the preferred treatment to decrease breast cancer risk depends on risk status.…”

Section: Discussionsupporting

confidence: 55%

Vitamin D3 Treatment Influences PGE2 and TGFβ in Normal and Increased Breast Cancer Risk Women

Qin

Holick

Sörensen³

et al. 2016

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Abstract. Background Preclinical (3) and epidemiological (4) studies suggest that the anti-inflammatory agent celecoxib also reduces BCa risk. Celecoxib inhibits COX2 through direct binding to the molecule, preventing the conversion of arachidonic acid to PGE 2 and other PGs (5). 1,25(OH) 2 D3 is also reported to alter the transforming growth factor (TGF)β pathway, which is important for the prevention and progression of breast carcinogenesis (6).Breast cells have the enzymatic machinery to convert 25(OH)D3 to 1,25(OH) 2 D3 (7). Increasing circulating levels of 25(OH)D3 is thought to result in an increased production of 1,25(OH) 2 D3 locally within breast cells, which, in turn, can affect their proliferation and differentiation (7).Thus, there is potential for a synergistic effect of improving the vitamin D status with celecoxib in the breast, with the local production of 1,25(OH) 2 D3 acting to reduce production of COX2, celecoxib to prevent the conversion of arachidonic acid to PGE 2 and 1,25(OH) 2 D3 also increasing the metabolism of the PGE 2 produced. We previously reported in a preliminary study that 2,000 IU vitamin D (but not vitamin D plus celecoxib) significantly decreased PGE 2 in the breast nipple aspirate fluid (NAF) of normal-risk women (8). To validate our preliminary findings and to determine if they also applied to women at increased breast cancer risk, we now report our findings of a larger cohort of normal-risk women, as well as a cohort of high-risk women who received placebo, 400 IU vitamin D3, 2,000 IU vitamin D3 or 2,000 IU vitamin D3 plus celecoxib. We also evaluated, vitamin D binding 5347

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“…A more detailed kinetic study indicates the existence of a three-step kinetic mechanism for the selective inhibition of COX-2 by celecoxib. 101 The reversible association of diaryl heterocycle inhibitors with COX, measured by following the inhibition of consumption of molecular oxygen as arachidonic acid is oxygenated by COX-2, comprises two steps that may or may not appear kinetically distinct, depending on the relative magnitudes of the rate constants. 101 The selectivity of the inhibitors for COX-2 is derived from the contribution of a third pseudoirreversible step that leads to a tightly bound complex.…”

Section: Iii4 Diaryl Heterocycles (Sulfonamides and Methyl Sulfones)mentioning

confidence: 99%

“…101 The reversible association of diaryl heterocycle inhibitors with COX, measured by following the inhibition of consumption of molecular oxygen as arachidonic acid is oxygenated by COX-2, comprises two steps that may or may not appear kinetically distinct, depending on the relative magnitudes of the rate constants. 101 The selectivity of the inhibitors for COX-2 is derived from the contribution of a third pseudoirreversible step that leads to a tightly bound complex. The difference in the rate constants for association of diaryl heterocycles with COX-1 and COX-2 does not correlate to the differences in selectivity.…”

Section: Iii4 Diaryl Heterocycles (Sulfonamides and Methyl Sulfones)mentioning

confidence: 99%

Structural and Functional Basis of Cyclooxygenase Inhibition

2007

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A three-step kinetic mechanism for selective inhibition of cyclo-oxygenase-2 by diarylheterocyclic inhibitors

Cited by 56 publications

References 40 publications

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1

Vitamin D3 Treatment Influences PGE2 and TGFβ in Normal and Increased Breast Cancer Risk Women

Structural and Functional Basis of Cyclooxygenase Inhibition

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