Anthracycline Cardiotoxicity: Worrisome Enough to Have You Quaking?

Abstract

In this issue, Gupta et al1 describe a novel mechanism, mediated through alterations in the RNA-binding protein QKI (Quaking), responsible for anthracycline-mediated cardiotoxicity. Performing global transcriptional profiling in murine hearts exposed to doxorubicin, they identified 5 differentially expressed RNA-binding proteins: 4 of which were upregulated and 1 QKI which was downregulated. QKI expression was decreased both in vitro (in rodent cardiomyocytes and in human induced pluripotent stem cell–derived cardiomyocytes) and in vivo in doxorubicin-treated mice. To confirm the role of QKI in mediating doxorubicin cardiotoxicity, Gupta et al1 showed that QKI small interfering RNA knockdown in primary cardiomyocytes increased doxorubicin-induced apoptosis; in contrast, lentiviral overexpression decreased apoptosis. Translating their findings to an in vivo model, they overexpressed Qki5 , the most abundant cardiac isoform, in murine hearts using AAV9 (adeno-associated virus) and showed a decrease in apoptosis as well as improved echocardiographic cardiac function. Finally, to further explore the mechanism of QKI’s modulation of cardiotoxicity, they identified QKI-regulated expression of several circular RNAs and demonstrated that inhibition of one, Ttn-derived circular RNA, increased doxorubicin cardiotoxicity. Thus, Gupta et al1 have demonstrated a role for the RNA-binding protein QKI as a mediator of anthracycline cardiotoxicity, suggesting a potential new target for intervention to prevent this life-threatening complication of anticancer treatment. Article, see p 246 The anthracyclines are some of the oldest anticancer agents in use today. First discovered in the 1950s, anthracyclines, such as doxorubicin, are still widely used in treating a range of malignancies and are included in half of breast cancer and two thirds of all childhood chemotherapy protocols. Anthracyclines have contributed to the dramatic increase in 5-year survival rates for childhood cancer, now >80%. However, as their use became widespread, the occurrence of a dose-dependent cardiotoxicity was recognized. The incidence of clinically significant left ventricular …