A characteristic component of the antineoplastic doxorubicin (DOX)-induced cardiac toxicity is the delayed and persistent toxicity, with cancer childhood survivors developing cardiac failure later in life. The mechanisms behind this persistent toxicity are unknown, although one of the consequences of early childhood treatment with DOX is a specific removal of cardiac progenitor cells. DOX treatment may be more toxic to undifferentiated muscle cells, contributing to impaired cardiac development and toxicity persistence. H9c2 myoblasts, a rat embryonic cell line, which has the ability to differentiate into a skeletal or cardiac muscle phenotype, can be instrumental in understanding DOX cytotoxicity in different differentiation stages. H9c2 cell differentiation results in decreased cell proliferation and increased expression of a differentiated muscle marker. Differentiated H9c2 cells accumulated more DOX and were more susceptible to DOX-induced cytotoxicity. Differentiated cells had increased levels of mitochondrial superoxide dismutase and Bcl-xL, an anti-apoptotic protein. Of critical importance for the mechanisms of DOX toxicity, p53 appeared to be equally activated regardless of the differentiation state. We suggest that although more differentiated H9c2 muscle cells appear to have more basal mechanisms that would predict higher protection, DOX toxicity is higher in the differentiated population. The results are instrumental in the understanding of stress responses of this specific cell line in different differentiation stages to the cardiotoxicity caused by anthracyclines.
Bibliographical noteFunding Information:
Acknowledgments The present work was funded by research grants from the Portuguese Foundation for Science and Technology (FCT) to PJO, PTDC/SAU-TOX/110952/2009, and PTDC/QUI/64358/2006 (COMPETE/FEDER/Portuguese National Funds). The FCT also supported AFB, ACM, and VAS through research fellowships (SFRH/BD/41384/2007, SFRH/BD/33892/2009, and SFRH/BPD/ 31549/2006). We are thankful to Alexandra Holy for proofreading the English language of the manuscript.
- Cardiac toxicity