title: 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 is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also proneoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced proneoplastic potential in comparison with the epidermal growth factor-like domain of neuregulin-1β (NRG), an effect mediated by receptor biasing toward ErbB3 homotypic interactions uncommonly formed by native neuregulin-1β. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced proneoplastic effects in comparison with NRG.
  
  
  RESULTS
  NN was expressed as a maltose-binding protein fusion in Escherichia coli. As established previously, NN stimulated antineoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated proneoplastic signaling and phenotype. In neonatal rat cardiomyocytes, NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in neonatal rat cardiomyocytes 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% versus 50.9±2.6%, P=0.004), whereas native NRG had no significant effect (49.4±3.7% versus 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 proneoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in patients with cancer receiving anthracyclines.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jay
authors.forename: Ashwin C
authors.initials: AC
authors.lastname: Murthy
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Hawkins
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Wortzel
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Steinhauser
authors.forename: Luis M
authors.initials: LM
authors.lastname: Alvarez
authors.forename: Joseph
authors.initials: J
authors.lastname: Gannon
authors.forename: Calum A
authors.initials: CA
authors.lastname: Macrae
authors.forename: Linda G
authors.initials: LG
authors.lastname: Griffith
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054715:Cardiotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002616:Chemical Engineering / Q000379:methods*; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D020890:Neuregulin-1 / Q000235:genetics* / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D016037:Single-Blind Method
chemical_list: D002316:Cardiotonic Agents; D054715:Cardiotoxins; D020890:Neuregulin-1; C117467:neuregulin beta; D004317:Doxorubicin
keywords: anthracyclines; protein engineering; translational cancer chemotherapy protocols