Mechanisms and management of doxorubicin-induced cardiotoxicity

Doxorubicin (DOX), a topoisomerase II inhibitor that is commonly used to treat childhood and adult cancer, induces p53-mediated cardiomyocyte apoptosis and heart failure. Heart failure could occur many years after termination of doxorubicin treatment. In an effort to test the hypothesis that cardiac-restricted expression of a dominant interfering p53 mutant (CB7) would protect cardiomyocytes from doxorubicin-induced apoptosis in vivo, we induced doxorubicin-dependent cardiotoxicity in adult (4-month old) and juvenile (2-week old) mice. Our results confirmed that cardiac-restricted inhibition of p53 transgene protects against doxorubicin-induced apoptosis in vivo and preserves heart function. However, the magnitude of the effect on cardiac function appeared disproportionate to the magnitude of the effect on cardiomyocyte apoptosis, suggesting that antagonism of p53 may engender additional cardioprotective activity. Further studies revealed that cardiac atrophy is an important mechanism for the heart dysfunction following doxorubicin treatment. Doxorubicin induces cardiac atrophy by inhibiting mammalian target of rapamycin (mTOR) and initiation factors for protein synthesis. Cardiac expression of CB7 protects against doxorubicin-induced inhibition of mTOR. To better elucidate the role of mTOR in doxorubicin-induced cardiotoxicity, we utilized mTORca transgenic mice which carries a cardiac-restricted expression of constitutively active mTOR and their non-transgenic littermates for doxorubicin treatment. Our data revealed that cardiac expression of mTORca enhances the activity of initiation factors and protects against doxorubicin-induced cardiac atrophy. These findings uncovered a translational regulatory mechanism of doxorubicin-induced cardiotoxicity by linking p53 to mTOR and initiation of cardiomyocyte protein synthesis.