An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity With Reduced Proneoplastic Potential
ABSTRACT BACKGROUND: Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1β (NRG1B) is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also pro-neoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced pro-neoplastic potential compared to the epidermal growth factor (EGF)-like domain of NRG1B (NRG), an effect mediated by receptor biasing towards ErbB3 homotypic interactions uncommonly formed by native NRG1B. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced pro-neoplastic effects compared to NRG. METHODS AND RESULTS: NN was expressed as a maltose-binding protein fusion in E. coli. As established previously, NN stimulated anti-neoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated pro-neoplastic signaling and phenotype. In neonatal rat cardiomyocytes (NRCM), NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in NRCM and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7% ± 0.6% vs. 50.9% ± 2.6%, P=0.004), whereas native NRG had no significant effect (49.4% ± 3.7% vs. 50.9% ± 2.6%, P=0.813). CONCLUSIONS: NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced pro-neoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in cancer patients receiving anthracyclines.
- [Show abstract] [Hide abstract]
ABSTRACT: Since their first discovery nearly 50 years ago(1), anthracyclines, including doxorubicin (Adriamycin), daunorubicin (Cerubidine), epirubicin (Ellence) and idarubicin (Idamycin PFS) have been successfully developed as potent anti-cancer therapeutics with significant efficacy in lymphomas and many solid tumors. Particularly in patients with breast cancer, they are the primary choices of therapy. However, cardiotoxicity has been a central limiting complication in treating patients since the agents acutely produce arrhythmias, LV dysfunction, and pericarditis, and chronically lead to LV dysfunction and heart failure(2). The toxicity is clearly dose-related with sharp rises in LV dysfunction with cumulative doses above 400-450 mg/m(2) for doxorubicin.(3) When cardiac imaging was employed, the incidence of HF was 5%, 26%, and 48% in patients receiving 400, 550, and 700 mg/m(2) of doxorubicin. As a result, most oncologists typically limit the dose to 450-500 mg/m(2). Children are especially vulnerable with rates of significant LV dysfunction of 5% at 15 yrs of follow-up, increasing to 10% for cumulative doses of ≥550 mg/m(2) (4). Heart failure may present many years after treatment. Mediastinal irradiation is an additional risk factor that may also be particularly problematic in children(5). To date, our only proven protective measure is adherence to "stopping guidelines" for total dose. Unfortunately, this typically limits the total dose an individual patient could receive, and for particularly problematic cancers, oncologists would like to use higher doses.Circulation 06/2013; 128(2). DOI:10.1161/CIRCULATIONAHA.113.003688 · 14.95 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: A number of new and innovative approaches for repairing damaged myocardium are currently undergoing investigation, with several encouraging results. In addition to the progression of stem cell-based approaches and gene therapy/silencing methods, evidence continues to emerge that protein therapeutics may be used to directly promote cardiac repair and even regeneration. However, proteins are often limited in their therapeutic potential by short local half-lives and insufficient bioavailability and bioactivity, and many academic laboratories studying cardiovascular diseases are more comfortable with molecular and cellular biology than with protein biochemistry. Protein engineering has been used broadly to overcome weaknesses traditionally associated with protein therapeutics and has the potential to specifically enhance the efficacy of molecules for cardiac repair. However, protein engineering as a strategy has not yet been used in the development of cardiovascular therapeutics to the degree that it has been used in other fields. In this review, we discuss the role of engineered proteins in cardiovascular therapies to date. Further, we address the promise of applying emerging protein engineering technologies to cardiovascular medicine and the barriers that must be overcome to enable the ultimate success of this approach.Circulation Research 09/2013; 113(7):933-43. DOI:10.1161/CIRCRESAHA.113.300215 · 11.09 Impact Factor
- Heart, Lung and Circulation 11/2013; 22(12). DOI:10.1016/j.hlc.2013.10.091 · 1.17 Impact Factor