Doxorubicin suppresses flow-dependent programs critical for endothelial cell function
Long-term survivors of childhood cancer (SCC) are at increased risk for cardiovascular disease (CVD), and CVD-related mortality. Anthracyclines are used in childhood cancer patients, and its cardiotoxic effects are well-established. Clinical evidence has documented a relationship between vascular impairment and anthracycline treatment; however, the mechanisms behind these effects are mostly unknown. Notably, endothelial cell dysfunction has been reported in SCC treated with anthracyclines, indicating a potential endothelial etiology of the side effects of these types of drugs. The transcription factor Kruppel-like factor 2 (KLF2) act as transcriptional integrator of flow- dependent endothelial function. Low doses of the anthracycline Doxorubicin (DOXO) block the flow-mediated expression of KLF2, and downstream targets related to vasomotor tone, inflammation, and thrombosis in cultured human endothelial cells (EC). Genome-wide expression profiling identified DOXO-mediated dysregulation of flow-dependent genes and programs. Importantly, since cancer patients experience multiple chemotherapeutic cycles, we have begun to explore the impact of multiple DOXO cycles treatments on endothelial cell structure and functional phenotype. Collectively, these studies identified a novel mechanistic link between flow-dependent endothelial function and the off-target effects of chemotherapeutic agents and could help in the development on new therapeutic interventions against cardiovascular disease in cancer patients.