Targeting Cyclooxygenase-2 and the Epidermal Growth Factor Receptor for the Prevention and Treatment of Intestinal Cancer

Buchanan, F. Gregory; Holla, Vijay; Katkuri, Sharada; Matta, Pranathi; DuBois, Raymond N.

doi:10.1158/0008-5472.can-07-0710

Cited by 66 publications

(47 citation statements)

References 20 publications

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“…The cardiotoxicity of COX-2 inhibitors has been considered to result from the suppression of prostaglandin synthesis in endothelial cells [9,10] . Reduced prostaglandin in blood vessels would prevent vasorelaxation and facilitate clot formation, and thus predispose patients with existing heart diseases higher chances of myocardial infarction [11,12] .…”

Section: Discussionmentioning

confidence: 99%

Possible arrhythmiogenic mechanism produced by ibuprofen

Yang

Wang

Zheng

et al. 2008

Acta Pharmacologica Sinica

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Aim: The aim of the present study was to investigate the electrophysiological effect of ibuprofen on the cardiac action potentials (AP) and electrocardiograms (ECG), and to identify its arrhythmiogenic mechanism. Methods: The intracellular microelectrode recording technique was employed to record the fast-and slowresponse AP in guinea pig papillary muscles. The cardiac responses of ibuprofen were monitored by ECG, both in in vivo and in vitro studies. Results: The ECG recording revealed that ibuprofen could induce arrhythmias, both in vitro and in vivo. Fatal ventricular fibrillations are readily produced in in vitro experiments by ibuprofen. Our results show that ibuprofen could dose dependently shorten the duration of AP and the effective refractory period (ERP), and it could also decrease the maximum depolarization velocity of phase 0 (V max ) in both the fast-and slow-response AP. The duration of the QRS complex wave (QRS duration) in ECG was prolonged. Although the heart rate was depressed by ibuprofen, the corrected QT interval duration (QTc) decreased. Conclusion: Ibuprofen could inhibit cardiac Na + and Ca 2+ channels as it slows V max in both fast-and slowresponse AP. Furthermore, ibuprofen shortens the ERP and decreases the excitation propagation within the heart, which might provide a substrate for an arrhythmiogenic re-entry circuit. Taken together, we conclude that ibuprofen, when used improperly, may impose a potential hazard in inducing cardiac arrhythmias in patients with existing heart diseases.

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Section: Discussionmentioning

confidence: 99%

Possible arrhythmiogenic mechanism produced by ibuprofen

Yang

Wang

Zheng

et al. 2008

Acta Pharmacologica Sinica

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“…The serum-starved cells were then washed three times with DMEM, including 0.2% FBS, to remove the aspirin and then were serum-stimulated by incubation in DMEM, including 20% FBS, to induce muCOX-2 protein. After 3 h, the medium was removed and replaced with 2 ml of MEM containing 10% FBS and 10 nmol of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]arachidonic acid (ϳ300,000 cpm) and incubated for 10 min at room temperature. Subsequently, 1 N citric acid and 10% butylated hydroxytoluene were added to stop the reaction (21), and prostaglandins were extracted from cell suspension by adding 8 ml of hexane/ethyl acetate (1:1, v/v) and centrifuged to separate the phases for 10 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…Both the enzymatic properties and the patterns of expression of the isoforms contribute to their unique functions (12). In part because of the association of COX-2 expression with pathologies such as inflammation and colon cancer (13)(14)(15), many studies have been performed to elucidate the mechanisms of transcriptional regulation of COX-2 as reviewed recently (6,7). It is now also clear that COX-2 is regulated post-transcriptionally at the level of both mRNA degradation (16) and protein degradation (17,18).…”

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confidence: 99%

Two Pathways for Cyclooxygenase-2 Protein Degradation in Vivo

Wada

Saunders

Morrow

et al. 2009

Journal of Biological Chemistry

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COX-2, formally known as prostaglandin endoperoxide H synthase-2 (PGHS-2), catalyzes the committed step in prostaglandin biosynthesis. COX-2 is induced during inflammation and is overexpressed in colon cancer. In vitro, an 18-amino acid segment, residues 595-612, immediately upstream of the C-terminal endoplasmic reticulum targeting sequence is required for N-glycosylation of Asn 594 , which permits COX-2 protein to enter the endoplasmic reticulum-associated protein degradation system. To determine the importance of this COX-2 degradation pathway in vivo, we engineered a del595-612 PGHS-2 (⌬18 COX-2) knock-in mouse lacking this 18-amino acid segment. ⌬18 COX-2 knock-in mice do not exhibit the renal or reproductive abnormalities of COX-2 null mice. ⌬18 COX-2 mice do have elevated urinary prostaglandin E 2 metabolite levels and display a more pronounced and prolonged bacterial endotoxin-induced febrile response than wild type (WT) mice. Normal brain tissue, cultured resident peritoneal macrophages, and cultured skin fibroblasts from ⌬18 COX-2 mice overexpress ⌬18 COX-2 relative to WT COX-2 expression in control mice. These results indicate that COX-2 can be degraded via the endoplasmic reticulum-associated protein degradation pathway in vivo. Treatment of cultured cells from WT or ⌬18 COX-2 mice with flurbiprofen, which blocks substrate-dependent degradation, attenuates COX-2 degradation, and treatment of normal mice with ibuprofen increases the levels of COX-2 in brain tissue. Thus, substrate turnover-dependent COX-2 degradation appears to contribute to COX-2 degradation in vivo. Curiously, WT and ⌬18 COX-2 protein levels are similar in kidneys and spleens from WT and ⌬18 COX-2 mice. There must be compensatory mechanisms to maintain constant COX-2 levels in these tissues.

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“…6 ( 11-13, 28, 29, 33, 34 ); however, we have not examined the specifi c steps involved, and of the AA-derived, 2-series PGs are widely accepted as relatively convenient indicators of whole-body PG synthesis. LC-MS/MS (multiple reaction monitoring) and ELISA methods are available to quantify PGE 2 , PGI 2 , and TxA 2 metabolites as tetranor PGE2M ( 11,30 ), 2,3-dinor-6-keto-PGF 1 ␣ (PGI2M) ( 17,31 ), and 11-dehydro-TxB 2 or 2,3-dinor-TxB 2 ( 14, 32 ), respectively.…”

Section: Characteristic Ions Corresponding To the Loss Of The Methoximentioning

confidence: 99%

Major urinary metabolites of 6-keto-prostaglandin F2α in mice

Kuklev

Hankin

Uhlson

et al. 2013

Journal of Lipid Research

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National Institutes of Health has taken the position that the evidence is inconclusive .The omega-3/omega-6 fatty acid "tone" of experimental animals or of humans ingesting nonprescription fi sh oil tablets or prescription supplements (Lovaza®) can be determined by measuring the ratio of omega-3 to omega-6 fatty acids in blood or in red blood cell membranes. Commercial kits are available for these relatively simple blood tests that involve quantifying fatty acid levels in plasma ( 4 ) or fatty acyl compositions of red blood cell lipids ( 5 ). Unfortunately, there is no validated method for estimating tissue levels of omega-3 versus omega-6 fatty acids noninvasively, such as by measuring appropriate metabolites in the urine.Prostaglandins (PG) can be formed from either arachidonic acid (AA), an omega-6 fatty acid, or from EPA, an omega-3 fatty acid, through the sequential actions of a phospholipase A 2 , cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2), and a PG synthase ( 6-10 ). Methods are available for measuring 2-series urinary PG metabolites formed from AA, including the major PGE 2 metabolite (PGEM) tetranor ( 11 ), two dinor metabolites of prostacyclin ( 12 ) and PGD 2 ( 13 ), and thromboxane B 2 metabolites ( 14 ). We reasoned that quantifi cation of a major urinary 3-series PG metabolite(s) of EPA in conjunction with measuring an appropriate 2-series PG metabolite might prove useful in estimating the AA/EPA ratio in tissue phospholipid precursors of PGs.Previous examination of the major urinary metabolites of PGE 3 performed in rats indicated that one of the metabolites is the tetranor derivative of PGE 3 formed via two steps of Abstract Western diets are enriched in omega-6 vs. omega-3 fatty acids, and a shift in this balance toward omega-3 fatty acids may have health benefi ts. There is limited information about the catabolism of 3-series prostaglandins (PG) formed from eicosapentaenoic acid (EPA), a fi sh oil omega-3 fatty acid that becomes elevated in tissues following fi sh oil consumption. Quantifi cation of appropriate urinary 3-series PG metabolites could be used for noninvasive measurement of omega-3 fatty acid tone. Here we describe the preparation of tritium-and deuterium-labeled 6-keto-PGF 2 ␣ and their use in identifying urinary metabolites in mice using LC-MS/MS. The major 6-keto-PGF 2 ␣ urinary metabolites included dinor-6-keto-PGF 2 ␣ ( ‫ف‬ 10%) and dinor-13, 14-dihydro-6,15-diketo-PGF 1 ␣ ( ‫ف‬ 10%). These metabolites can arise only from the enzymatic conversion of EPA to the 3-series PGH endoperoxide by cyclooxygenases, then PGI 3 by prostacyclin synthase and, fi nally, nonenzymatic hydrolysis to 6-keto-PGF 2 ␣ . The 6-keto-PGF derivatives are not formed by free radical mechanisms that generate isoprostanes, and thus, these metabolites provide an unbiased marker for utilization of EPA by cyclooxygenases. -Kuklev,

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Targeting Cyclooxygenase-2 and the Epidermal Growth Factor Receptor for the Prevention and Treatment of Intestinal Cancer

Cited by 66 publications

References 20 publications

Possible arrhythmiogenic mechanism produced by ibuprofen

Possible arrhythmiogenic mechanism produced by ibuprofen

Two Pathways for Cyclooxygenase-2 Protein Degradation in Vivo

Major urinary metabolites of 6-keto-prostaglandin F2α in mice

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