title: Nutrition Modulation of Cardiotoxicity and Anticancer Efficacy Related to Doxorubicin Chemotherapy by Glutamine and ω-3 Polyunsaturated Fatty Acids.
abstract: BACKGROUND
  Doxorubicin (DOX) has been one of the most effective antitumor agents against a broad spectrum of malignancies. However, DOX-induced cardiotoxicity forms the major cumulative dose-limiting factor. Glutamine and ω-3 polyunsaturated fatty acids (PUFAs) are putatively cardioprotective during various stresses and/or have potential chemosensitizing effects during cancer chemotherapy.
  
  
  METHODS
  Antitumor activity and cardiotoxicity of DOX treatment were evaluated simultaneously in a MatBIII mammary adenocarcinoma tumor-bearing rat model treated with DOX (cumulative dose 12 mg/kg). Single or combined treatment of parenteral glutamine (0.35 g/kg) and ω-3 PUFAs (0.19 g/kg eicosapentaenoic acid and 0.18 g/kg docosahexaenoic acid) was administered every other day, starting 6 days before chemotherapy initiation until the end of study (day 50).
  
  
  RESULTS
  Glutamine alone significantly prevented DOX-related deterioration of cardiac function, reduced serum cardiac troponin I levels, and diminished cardiac lipid peroxidation while not affecting tumor inhibition kinetics. Single ω-3 PUFA treatment significantly enhanced antitumor activity of DOX associated with intensified tumoral oxidative stress and enhanced tumoral DOX concentration while not potentiating cardiac dysfunction or increasing cardiac oxidative stress. Intriguingly, providing glutamine and ω-3 PUFAs together did not consistently confer a greater benefit; conversely, individual benefits on cardiotoxicity and chemosensitization were mostly attenuated or completely lost when combined.
  
  
  CONCLUSIONS
  Our data demonstrate an interesting differentiality or even dichotomy in the response of tumor and host to single parenteral glutamine and ω-3 PUFA treatments. The intriguing glutamine × ω-3 PUFA interaction observed draws into question the common assumption that there are additive benefits of combinations of nutrients that are beneficial on an individual basis.
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado Hongyu.Xue@ucdenver.edu.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Ren
authors.affiliation: Fresenius Kabi, Bad Homburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Denkinger
authors.affiliation: Fresenius Kabi, Bad Homburg, Germany.
authors.forename: Ewald
authors.initials: E
authors.lastname: Schlotzer
authors.affiliation: Department of Anesthesiology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wischmeyer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001119:Arginase / Q000378:metabolism; D066126:Cardiotoxicity / Q000188:drug therapy*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects*; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D005973:Glutamine / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006706:Homeostasis; D015227:Lipid Peroxidation / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D009752:Nutritional Status; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D016896:Treatment Outcome; D014336:Troponin / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D015525:Fatty Acids, Omega-3; D018840:HSP70 Heat-Shock Proteins; D014336:Troponin; D005973:Glutamine; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; C505410:Casp3 protein, rat; D053148:Caspase 3; D001119:Arginase
keywords: amino acids; breast cancer; cardiotoxicity; doxorubicin; fatty acids; glutamine; oncology; research and diseases