Metformin protects against sunitinib-induced cardiotoxicity: Investigating the role of AMPK

Refik Kuburas, Mayel Gharanei, Irmgard Haussmann, H Maddock, Hardip Sandhu

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    Abstract

    Sunitinib is associated with cardiotoxicity through inhibition of AMP-protein kinase (AMPK) signalling. In contrast, the common anti-diabetic agent metformin has demonstrated cardioprotection via indirect AMPK activation. Here we investigate the effects of metformin during sunitinib-induced cytotoxicity. Left ventricular developed pressure (LVDP), coronary flow (CF), heart rate (HR) and infarct size was measured in Langendorff perfused rat hearts treated with 1 µM sunitinib ± 50 µM metformin ± 1 µM human equilibrative nucleoside transporter inhibitor S-(4-Nitrobenzyl)-6-thionosine (NBTI). Western blot analysis was carried out for p-AMPKα levels. Primary isolated cardiac myocytes from the left ventricular tissue were used to measure live cell population levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to assess adjunctive treatment of and metformin in human hepatoma G2 (HepG2) and promyelocytic leukaemia (HL-60) cells treated with 0.1-100 µM sunitinib ± 50 µM metformin. In the perfused hearts co-administration of metformin attenuated the sunitinib-induced changes to LVDP, infarct size and cardiac myocyte population. Western blot analysis revealed a significant decrease in p-AMPKα during sunitinib treatment, which was attenuated following co-administration with metformin. All metformin-induced effects were attenuated NBTI was co-administered. The MTT assay demonstrated an increase in the EC50-value during co-administration of metformin with sunitinib compared to sunitinib mono-therapy in HepG2 and HL-60 cell lines, demonstrating the impact and complexity of metformin co-administration and the possible role of AMPK signalling. This study highlights the novel cardioprotective properties of metformin and AMPK activation during sunitinib-induced cardiotoxicity when administered together in the Langendorff heart model.
    Original languageEnglish
    Pages (from-to)799-807
    Number of pages9
    JournalJournal of Cardiovascular Pharmacology
    Volume79
    Issue number6
    Early online date8 Mar 2022
    DOIs
    Publication statusE-pub ahead of print - 8 Mar 2022

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    This document is the author’s post-print version, incorporating any revisions agreed during the peer-review process. Some differences between the published version and this version may remain and you are advised to consult the published version if you wish to cite from it.

    Keywords

    • sunitinib
    • metformin
    • AMP-protein kinase
    • cardiotoxicity
    • cardioprotection
    • cardiac myocytes

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