title: The Cardioprotective Role of N-Acetyl Cysteine Amide in the Prevention of Doxorubicin and Trastuzumab-Mediated Cardiac Dysfunction.
abstract: In the breast cancer setting, anticancer therapies including doxorubicin (DOX) and trastuzumab (TRZ) are associated with a significantly increased risk of cardiotoxicity. Despite the increasing support for the role of oxidative stress (OS) in its pathophysiology, we still do not have an optimal antioxidant for the prevention of DOX + TRZ-mediated cardiac dysfunction. The objective of this study was to investigate whether the novel antioxidant N-acetylcysteine amide (NACA) can attenuate DOX + TRZ-induced heart failure in a murine model.
  
  
  
  A total of 100 C57Bl/6 female mice received 1 of the following drug regimens: (1) saline, (2) NACA, (3) DOX, (4) TRZ, (5) DOX + TRZ, (6) NACA + DOX, (7) NACA + TRZ, and (8) NACA + DOX + TRZ. Serial echocardiography was performed over a 10-day study period, after which the mice were killed for histologic and biochemical analyses.
  
  
  
  In mice receiving DOX, the left ventricular ejection fraction (LVEF) decreased from 73% ± 4% to 43% ± 2% on day 10. In mice receiving DOX + TRZ, the LVEF decreased from 72% ± 3% to 32% ± 2% on day 10. Prophylactic administration of NACA to mice receiving DOX or DOX + TRZ was cardioprotective, with an LVEF of 62% ± 3% and 55% ± 3% on day 10, respectively. Histologic and biochemical analyses demonstrated a loss of cellular integrity, increased OS, and increased cardiac apoptosis in mice treated with DOX + TRZ, which was attenuated by the prophylactic administration of NACA.
  
  
  
  NACA attenuated the cardiotoxic side effects of DOX + TRZ in a murine model of chemotherapy-induced cardiac dysfunction by decreasing OS and apoptosis.
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Vineet
authors.initials: V
authors.lastname: Goyal
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Hilary
authors.initials: H
authors.lastname: Bews
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Cheung
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Sheena
authors.initials: S
authors.lastname: Premecz
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Soma
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Bilal
authors.initials: B
authors.lastname: Shaikh
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Best
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhindi
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Chaudhary
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Amir
authors.initials: A
authors.lastname: Ravandi
authors.affiliation: Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Thliveris
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Singal
authors.affiliation: Sections of Oncology and Hematology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Saroj
authors.initials: S
authors.lastname: Niraula
authors.affiliation: Institute of Cardiovascular Sciences, St Boniface Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Cardiology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Sections of Oncology and Hematology, Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Radiology, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: djassal@sbgh.mb.ca.
authors.forename: Davinder S
authors.initials: DS
authors.lastname: Jassal
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000975:Antioxidants / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D066126:Cardiotoxicity / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D016903:Drug Monitoring; D004452:Echocardiography / Q000379:methods; D005260:Female; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D002316:Cardiotonic Agents; C487056:N-Acetylcysteinamide; D004317:Doxorubicin; D000068878:Trastuzumab; D000111:Acetylcysteine