Persistent Alterations to the Gene Expression Profile of the Heart Subsequent to Chronic Doxorubicin Treatment

Doxorubicin (DOX, Adriamycin^®) is a potent antineoplastic agent used to treat a number of cancers. Despite its utility, DOX causes a cumulative, irreversible cardiomyopathy that may become apparent shortly after treatment or years subsequent to therapy. Numerous studies have been conducted to elucidate the basis of DOX cardiotoxicity, but the precise mechanism responsible remains elusive. This investigation was designed to assess global gene expression using microarrays in order to identify the full spectrum of potential molecular targets of DOX cardiotoxicity to further delineate the underlying pathological mechanism(s) responsible for this dose-limiting cardiomyopathy. Male, Sprague-Dawley rats received 6 weekly injections of 2 mg/kg (s.c.) DOX followed by a 5 week drug-free period prior to analysis of cardiac tissue transcripts. Ontological evaluation in terms of subcellular targets identified gene products involved in mitochondrial processes are significantly suppressed, consistent with the well-established persistent mitochondrial dysfunction. Further classification of genes into biochemical networks revealed several pathways modulated by DOX, including glycolysis and fatty acid metabolism, supporting the notion that mitochondria are key targets in DOX toxicity. In conclusion, this comprehensive transcript profile provides important insights into critical targets and molecular adaptations that characterize the persistent cardiomyopathy associated with long-term exposure to DOX.