A Differential Effect of FGF‐2 on Resistance to Doxorubicin‐Induced Necrotic Versus Apoptotic‐Like Damage in Neonatal Rat Cardiomyocyte Cultures

Abstract

Therapeutic agents like doxorubicin (DOX), an anti‐cancer anthracycline, can increase the risk of cardiac damage. Strategies are needed to protect the heart that still allows the benefits of drug treatment. “Basic” fibroblast growth factor‐2 (FGF‐2), and specifically the low (18 kDa) molecular weight isoform is cardioprotective, but this has not been reported for DOX‐induced injury. The clinical effects of DOX have been modeled in rat cardiomyocytes, and 0.1–1.0 μM DOX is sufficient to induce cell damage. Here, we assessed the effect of 10 nM FGF‐2 on 0.5 μM DOX‐induced necrotic versus apoptotic‐related damage over 24 hours, as detected by the presence of lactate dehydrogenase in the culture medium (LDH) versus DNA fragmentation by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). DOX induced a decrease in apparent (attached) cell number and a significant increase in LDH within 6 hours. The remaining cells continued to display muscle striations based on alpha‐actinin staining, but an increase in TUNEL intensity from 6 to 24 hours was also seen. Pre‐treatment (30 min) with FGF‐2 resulted in a significant decrease in LDH but not apparent TUNEL intensity. Additional assays to characterize these effects are being pursued. These data suggest that FGF‐2 can increase resistance to DOX‐induced plasma membrane damage but not DNA fragmentation under the conditions tested.