Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo.
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.
Dowd
N P
NP
Department of Anaesthesia and Intensive Care, Beaumont Hospital, Dublin, Ireland.
Scully
M
M
Adderley
S R
SR
Cunningham
A J
AJ
Fitzgerald
D J
DJ
D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives* / Q000652:urine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology*; D015415:Biomarkers; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D011464:Epoprostenol / Q000096:biosynthesis / Q000502:physiology; D006321:Heart / Q000187:drug effects*; D016285:Iloprost / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008565:Membrane Proteins; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology* / Q000633:toxicity*; D013929:Thromboxane B2 / Q000097:blood; D014157:Transcription Factors / Q000378:metabolism; D020107:Troponin T / Q000097:blood; D000096926:Benzenesulfonamides
D015121:6-Ketoprostaglandin F1 alpha; D016718:Arachidonic Acid; D001241:Aspirin; D015415:Biomarkers; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004317:Doxorubicin; D011464:Epoprostenol; D016285:Iloprost; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D013929:Thromboxane B2; D014157:Transcription Factors; D020107:Troponin T; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C115461:SC 560; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; C496513:Ptgs1 protein, rat