Early effects of acute doxorubicin treatment include increased apical caspase expression and activation in liver, but not heart, of fasted animals

Abstract

Doxorubicin (DOX) is an effective chemotherapeutic agent, but known to cause cardiotoxicitv via induction of oxidative stress and apoptosis. DOX also causes hepatic toxicity, although mechanisms have not been as extensively described. Currently, the mechanism of DOX induced hepatic apoptosis is unknown. Moreover, despite the anorexic effects of DOX very few studies have controlled for this and, therefore, it is not clear whether changes in apoptosis markers and signaling in vivo are due to direct or indirect effects of DOX. Thus, we aimed to determine the early effects of DOX on expression and activation of apical caspases in heart and liver and to delineate these effects from mal consumption of food and water. Male F344 rats were injected IP with 20 mg/kg of DOX or saline. Once treated, all animals were fasted with no food or water until sacrifice 24 hours later. DOX did not affect expression or activation of caspase‐1, ‐8, ‐9, ‐12 in the heart at 24‐hour post treatment. However, DOX increased procaspase‐9 expression and caspase‐12 activation in liver. These results may suggest that at an early time point after acute DOX administration, the liver seems more vulnerable to DOX‐induced apoptosis compared to the heart. This may be explained by higher concentrations of DOX in liver compared to heart and/or the increased resistance to apoptosis in post‐mitotic cardiomyocytes compared to mitotic hepatocytes.