Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo

The clinical use of doxorubicin, an anthracycline chemotherapeutic agent, i s 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 th at the administration of a prostaglandin may protect the heart during the i n vivo administration of doxorubicin. Doxorubicin (15 mg/kg) administered t o adult male Sprague Dawley rats induced COX-2 expression and activity in c ardiac tissue. Prostacyclin generation measured as the excretion of 2,3-din or-6-keto-PGF(1 alpha) also increased, and this was blocked by a COX-2 inhi bitor, SC236. In contrast, administration of a COX-1 inhibitor SC560 at a d ose that reduced serum thromboxane B-2 by more than 80% did not prevent the doxorubicin-induced increase in prostacyclin generation. Doxorubicin incre ased 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 t reated 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 doxorubici n by prior administration of prostacyclin.