Abstract
The clinical use of doxorubicin, an anthracycline chemotherapeutic agent, is limited by cardiotoxicity, particularly when combined with herceptin, an antibody that blocks the HER2 receptor. Doxorubicin induces cyclooxygenase-2 (COX-2) activity in rat neonatal cardiomyocytes. This expression of COX-2 limits doxorubicin-induced cardiac cell injury, raising the possibility that the administration of a prostaglandin may protect the heart during the in vivo administration of doxorubicin. Doxorubicin (15 mg/kg) administered to adult male Sprague Dawley rats induced COX-2 expression and activity in cardiac tissue. Prostacyclin generation measured as the excretion of 2,3-dinor-6-keto-PGF(1alpha) also increased, and this was blocked by a COX-2 inhibitor, SC236. In contrast, administration of a COX-1 inhibitor SC560 at a dose that reduced serum thromboxane B2 by more than 80% did not prevent the doxorubicin-induced increase in prostacyclin generation. Doxorubicin increased cardiac injury, detected as a rise in plasma cardiac troponin T, serum lactate dehydrogenase, and cardiomyocyte apoptosis; this was aggravated by coadministration of SC236 but not SC560. The degree of injury in animals treated with a combination of doxorubicin and SC236 was attenuated by prior administration of the prostacyclin analogue iloprost. These data raise the possibility of protecting the heart during the administration of doxorubicin by prior administration of prostacyclin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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6-Ketoprostaglandin F1 alpha / analogs & derivatives*
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6-Ketoprostaglandin F1 alpha / urine
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Animals
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Apoptosis / drug effects
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Arachidonic Acid / pharmacology
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Aspirin / pharmacology*
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Biomarkers
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Cardiomyopathies / chemically induced*
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Cardiomyopathies / metabolism
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Cardiomyopathies / prevention & control
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Cyclooxygenase 1
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Cyclooxygenase Inhibitors / toxicity*
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Doxorubicin / pharmacology
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Doxorubicin / toxicity*
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Enzyme Induction / drug effects
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Epoprostenol / biosynthesis
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Epoprostenol / physiology
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Heart / drug effects*
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Iloprost / therapeutic use
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Isoenzymes / antagonists & inhibitors*
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Isoenzymes / biosynthesis
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Isoenzymes / genetics
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Isoenzymes / physiology
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L-Lactate Dehydrogenase / blood
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Male
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Membrane Proteins
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Myocardium / metabolism
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Myocardium / pathology*
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Nitrobenzenes / pharmacology*
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Prostaglandin-Endoperoxide Synthases / biosynthesis
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / physiology
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Pyrazoles / pharmacology
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Pyrazoles / toxicity*
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Rats
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Rats, Sprague-Dawley
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Receptors, Cytoplasmic and Nuclear / metabolism
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Sulfonamides / pharmacology*
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Sulfonamides / toxicity*
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Thromboxane B2 / blood
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Transcription Factors / metabolism
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Troponin T / blood
Substances
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4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
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Biomarkers
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Membrane Proteins
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Nitrobenzenes
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Pyrazoles
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Receptors, Cytoplasmic and Nuclear
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SC 560
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Sulfonamides
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Transcription Factors
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Troponin T
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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Arachidonic Acid
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Thromboxane B2
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6-Ketoprostaglandin F1 alpha
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2,3-dinor-6-ketoprostaglandin F1alpha
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Doxorubicin
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Epoprostenol
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L-Lactate Dehydrogenase
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Cyclooxygenase 1
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Cyclooxygenase 2
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Prostaglandin-Endoperoxide Synthases
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Ptgs1 protein, rat
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Iloprost
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Aspirin