Neuregulin1-ErbB Signaling in Doxorubicin-Induced Cardiotoxicity

This chapter will review basic and clinical findings regarding the cardioprotective role of Neuregulin1-ErbB signaling against the cardiotoxicity of doxorubicin, a widely used chemotherapeutic agent. In 2001, The New England Journal of Medicine published the results from clinical trials in breast cancer patients using Trastuzumab, a monoclonal antibody that blocks the ErbB2 receptor. These studies showed that the incidence of New York Heart Association (NYHA) class III/IV heart failure was 16% in patients who were concurrently treated with doxorubicin and Trastuzumab compared to 3% and 2% respectively in patients who were treated with doxorubicin or Trastuzumab alone (Slamon et al., 2001). These results for the first time suggest that the ErbB signaling has cardioprotective effects against doxorubicin-induced cardiotoxicity. Since then, a significant amount of basic and clinical research has been conducted to investigate the mechanisms of the ErbB signaling pathway in protecting the heart from doxorubicin-induced toxicity. At the same time, studies have been performed searching for factors that stimulate ErbB signaling to protect the heart from doxorubicin. Although ErbB receptors have at least 13 ligands, Neuregulin1 proteins have become the focus of this search (Yarden and Sliwkowski, 2001a). Studies from cardiomyocyte culture, animal models and clinical trials have demonstrated that Neuregulin1 may be effective for preventing or treating doxorubicin-induced cardiotoxicity.