Trimetazidine ameliorates sunitinib-induced cardiotoxicity in mice via the AMPK/mTOR/autophagy pathway.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read Online Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Taylor & Francis Country of Publication: England NLM ID: 9812552 Publication Model: Print Cited Medium: Internet ISSN: 1744-5116 (Electronic) Linking ISSN: 13880209 NLM ISO Abbreviation: Pharm Biol Subsets: MEDLINE
    • Publication Information:
      Publication: [London] : Taylor & Francis
      Original Publication: Lisse, the Netherlands : Swets & Zeitlinger, c1998-
    • Subject Terms:
      Hypertension/*drug therapy ; Sunitinib/*toxicity ; Trimetazidine/*pharmacology; AMP-Activated Protein Kinase Kinases ; Animals ; Apoptosis/drug effects ; Autophagy/drug effects ; Cardiotoxicity ; Cell Survival/drug effects ; Cells, Cultured ; Hypertension/chemically induced ; Male ; Mice ; Microtubule-Associated Proteins ; Myocytes, Cardiac/drug effects ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/metabolism ; Rats ; Signal Transduction/drug effects ; Sunitinib/pharmacology ; TOR Serine-Threonine Kinases/metabolism
    • Abstract:
      Context: Sunitinib (SU) is a multi-targeted tyrosine kinase inhibitor anticancer agent whose clinical use is often limited by cardiovascular complications. Trimetazidine (TMZ) is an anti-angina agent that has been demonstrated cardioprotective effects in numerous cardiovascular conditions, but its potential effects in SU-induced cardiotoxicity have not been investigated. Objective: This study investigates the effect of TMZ in sunitinib-induced cardiotoxicity in vivo and in vitro and molecular mechanisms. Materials and methods: Male 129S1/SvImJ mice were treated with vehicle, SU (40 mg/kg/d) or SU and TMZ (20 mg/kg/d) via oral gavage for 28 days, and cardiovascular functions and cardiac protein expressions were examined. H9c2 cardiomyocytes were treated with vehicle, SU (2-10 μM) or SU and TMZ (40-120 μM) for 48 h, and cell viability, apoptosis, autophagy, and protein expression was tested. Results: SU induces hypertension (systolic blood pressure [SBP] + 28.33 ± 5.00 mmHg) and left ventricular dysfunction (left ventricular ejection fraction [LVEF] - 11.16 ± 2.53%) in mice. In H9c2 cardiomyocytes, SU reduces cell viability (IC 50 4.07 μM) and inhibits the AMPK/mTOR/autophagy pathway ( p  < 0.05). TMZ co-administration with SU reverses SU-induced cardiotoxicity in mice (SBP - 23.75 ± 4.69 mmHg, LVEF + 10.95 ± 3.317%), alleviates cell viability loss in H9c2 cardiomyocytes ( p  < 0.01) and activates the AMPK/mTOR/autophagy pathway in vivo ( p  < 0.001) and in vitro ( p  < 0.05). Discussion and conclusions: Our results suggest TMZ as a potential cardioprotective approach for cardiovascular complications during SU regimen, and potentially for cardiotoxicity of other anticancer chemotherapies associated with cardiomyocyte autophagic pathways.
    • References:
      Cancer Lett. 2018 Oct 28;435:32-43. (PMID: 30055290)
      J Histochem Cytochem. 2000 Jul;48(7):963-70. (PMID: 10858273)
      J Mol Med (Berl). 2018 Aug;96(8):791-806. (PMID: 29955901)
      FEBS J. 2013 Oct;280(20):5094-108. (PMID: 23953053)
      Br J Pharmacol. 2016 Feb;173(3):545-61. (PMID: 26566260)
      Cancer. 2015 May 1;121(9):1405-13. (PMID: 25641662)
      J Pineal Res. 2013 Aug;55(1):65-78. (PMID: 23551302)
      Curr Protoc Mouse Biol. 2011 Mar 1;1:71-83. (PMID: 21743841)
      Angiology. 2003 Mar-Apr;54(2):219-27. (PMID: 12678198)
      Clin Transl Sci. 2009 Feb;2(1):15-25. (PMID: 20376335)
      J Transl Med. 2018 Jul 9;16(1):190. (PMID: 29986726)
      Cancer Lett. 2018 Aug 28;430:133-147. (PMID: 29777783)
      Am J Physiol Heart Circ Physiol. 2015 Nov;309(9):H1453-67. (PMID: 26386112)
      J Cardiovasc Pharmacol. 2017 Jun;69(6):389-397. (PMID: 28581448)
      Autophagy. 2016;12(1):1-222. (PMID: 26799652)
      Cardiovasc Ther. 2018 Oct;36(5):e12460. (PMID: 30019466)
      Eur J Cancer. 2017 May;76:110-117. (PMID: 28301826)
      Arch Toxicol. 2014 Mar;88(3):725-38. (PMID: 24247421)
      Eur J Cancer. 2014 Aug;50(12):2162-70. (PMID: 24930624)
      J Cachexia Sarcopenia Muscle. 2017 Dec;8(6):954-973. (PMID: 29130633)
      PLoS One. 2016 Feb 03;11(2):e0145937. (PMID: 26840448)
      Lancet. 2007 Dec 15;370(9604):2011-9. (PMID: 18083403)
      Int J Cardiol. 2017 May 1;234:1-6. (PMID: 28256321)
      Cardiovasc Toxicol. 2015 Jan;15(1):41-51. (PMID: 24984876)
      Mol Cancer Res. 2017 Mar;15(3):250-258. (PMID: 28184014)
      Ann Oncol. 2009 Sep;20(9):1535-42. (PMID: 19474115)
      Sci Transl Med. 2013 May 29;5(187):187ra69. (PMID: 23720580)
      Toxicol Appl Pharmacol. 2010 Oct 1;248(1):20-7. (PMID: 20637791)
      Heart Fail Rev. 2016 Sep;21(5):621-34. (PMID: 27230651)
      J Am Heart Assoc. 2017 Oct 19;6(10):null. (PMID: 29051215)
      J Transl Med. 2016 Apr 27;14(1):109. (PMID: 27121077)
      Clin Cancer Res. 2017 Jul 15;23(14):3601-3609. (PMID: 28196874)
      Drugs. 2014 Jun;74(9):971-80. (PMID: 24902800)
      Int J Cardiol. 2016 Jan 15;203:909-15. (PMID: 26618252)
    • Contributed Indexing:
      Keywords: Hypertension; cardiomyocyte; left ventricular dysfunction; tyrosine kinase inhibitor
    • Accession Number:
      0 (LC3 protein, rat)
      0 (Microtubule-Associated Proteins)
      0 (Protein Kinase Inhibitors)
      EC 2.7.- (Protein Kinases)
      EC 2.7.11.1 (TOR Serine-Threonine Kinases)
      EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
      N9A0A0R9S8 (Trimetazidine)
      V99T50803M (Sunitinib)
    • Publication Date:
      Date Created: 20190924 Date Completed: 20200326 Latest Revision: 20211204
    • Publication Date:
      20231215
    • Accession Number:
      PMC6764339
    • Accession Number:
      31545912