Cardiovascular Risk of Selective Cyclooxygenase-2 Inhibitors

Schrör, Karsten; Mehta, Paulette; Mehta, Jawahar L.

doi:10.1177/107424840501000203

Cited by 9 publications

(3 citation statements)

References 29 publications

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“…Although studies have suggested that COX-2 inhibition may be beneficial in cancer prevention, recent data raise concern regarding cardiovascular toxicities associated with the use of COX-2 inhibition (Schrör et al, 2005). An alternative approach that could potentially avoid this toxicity includes targeting other elements in the prostanoid pathway downstream of COX-2.…”

mentioning

confidence: 99%

Pioglitazone and Rosiglitazone Decrease Prostaglandin E₂ in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Hazra¹,

Batra²,

Tai³

et al. 2007

Mol Pharmacol

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Lung cancer cells elaborate the immunosuppressive and antiapoptotic mediator prostaglandin E 2 (PGE 2 ), a product of cyclooxygenase-2 (COX-2) enzyme activity. Because peroxisome proliferator-activated receptor (PPAR)␥ ligands, such as thiazolidinediones (TZDs), inhibit lung cancer cell growth, we examined the effect of the TZDs pioglitazone and rosiglitazone on PGE 2 levels in non-small-cell lung cancer (NSCLC) A427 and A549 cells. Both TZDs inhibited PGE 2 production in NSCLC cells via a COX-2 independent pathway. To define the mechanism underlying COX-2 independent suppression of PGE 2 production, we focused on other enzymes responsible for the synthesis and degradation of PGE 2 . The expression of none of the three prostaglandin synthases (microsomal PGES1, PGES2 and cystosolic PGES) was down-regulated by the TZDs. It is noteworthy that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that produces biologically inactive 15-ketoprostaglandins from active PGE 2 , was induced by TZDs. The TZD-mediated suppression of PGE 2 concentration was significantly inhibited by small interfering RNA to 15-PGDH. Studies using dominant-negative PPAR␥ overexpression or 2-chloro-5-nitrobenzanilide (GW9662; a PPAR␥ antagonist) revealed that the suppressive effect of the TZDs on PGE 2 is PPAR␥-independent. Together, these findings indicate that it is possible to use a clinically available pharmacological intervention to suppress tumor-derived PGE 2 by enhancing catabolism rather than blocking synthesis.Lung cancer is the major cause of cancer-related death in the United States. There is an overall 5-year survival of less than 15%, and thus new therapeutic strategies are needed (Parkin, 2001). Recent research has focused on targeted pathways operative in lung cancer pathogenesis.Increased cyclooxygenase expression (Huang et al., 1998) and elevated PGE 2 production have been implicated in the pathogenesis of several malignancies and are also associated with a poor prognosis in lung cancer (Wolff et al., 1998). Two isoenzymes of cyclooxygenase (COX) have been described: the constitutive enzyme COX-1 and the inducible enzyme COX-2. Elevated expression of COX-2 is found in a variety of malignant tissues, including colon, gastric, esophageal, prostate, breast, and lung carcinomas (Huang et al

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confidence: 99%

Pioglitazone and Rosiglitazone Decrease Prostaglandin E₂ in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Hazra¹,

Batra²,

Tai³

et al. 2007

Mol Pharmacol

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“…An incomplete and simplistic interpretation of the processes and mechanisms that regulate these important enzymes may have led to the initial poor understanding of the adverse events, followed by warnings and withdrawals, a lop-sided sequence in drug approval. The mechanism of action of the cyclooxygenases (COX) was first described by Vane (1971) and is summarized in Figure 1 [ Schrör et al 2005].…”

Section: Physiology Of the Cox Enzymesmentioning

confidence: 99%

“…Arachidonic acid metabolism via cyclooxygenase-1 and cyclooxygenase-2 in the cardiovascular system. Potential mechanisms for COX-2 inhibition related thrombosis and hypertension [Schrör et al 2005].…”

Section: Figurementioning

confidence: 99%

Review: Adverse cardiovascular effects of NSAIDs: driven by blood pressure, or edema?

Aneja¹,

Farkouh

2008

Therapeutic Advances in Cardiovascular Disease

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The non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are commonly utilized agents for musculoskeletal conditions. The harmful cardiorenal effects of some nsNSAIDs are well described and thought to be related to inhibition of prostanoid synthesis. Since the non-specific inhibition of both cyclooxygenase enzymes was associated with a higher incidence of gastrointestinal side effects, the selective targeting of the COX-2 enzymes with the COX-2 inhibitors promised and delivered a lower incidence of gastrointestinal side effects. However, the COX-2 inhibitors have not been found to be bereft of cardiorenal side effects. Indeed, some of these agents lead to increased blood pressure, an excessive risk of congestive heart failure and pro-thrombotic effects, especially in high risk populations. These deletrious effects, however, may not be class-specific and possibly related to pharmacokinetics, enzyme specificity and endothelium effects. This article also reviews the body of literature linking the nsNSAIDs and COX-2 inhibitors with important adverse cardiorenal effects and their putative mechanisms.

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Pharmacology

Schrör

2008

Acetylsalicylic Acid

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Cardiovascular Risk of Selective Cyclooxygenase-2 Inhibitors

Cited by 9 publications

References 29 publications

Pioglitazone and Rosiglitazone Decrease Prostaglandin E₂ in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Pioglitazone and Rosiglitazone Decrease Prostaglandin E₂ in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Review: Adverse cardiovascular effects of NSAIDs: driven by blood pressure, or edema?

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Cardiovascular Risk of Selective Cyclooxygenase-2 Inhibitors

Cited by 9 publications

References 29 publications

Pioglitazone and Rosiglitazone Decrease Prostaglandin E2 in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Pioglitazone and Rosiglitazone Decrease Prostaglandin E2 in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Review: Adverse cardiovascular effects of NSAIDs: driven by blood pressure, or edema?

Pharmacology

Contact Info

Product

Resources

About

Pioglitazone and Rosiglitazone Decrease Prostaglandin E₂ in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase

Pioglitazone and Rosiglitazone Decrease Prostaglandin E₂ in Non–Small-Cell Lung Cancer Cells by Up-Regulating 15-Hydroxyprostaglandin Dehydrogenase