Attenuation of Sunitinib-induced cardiotoxicity through the A3 adenosine receptor activation

Hardip Sandhu, Samantha Cooper, Afthab Hussain, Christopher Mee, Helen Maddock

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8 Citations (Scopus)
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Abstract

Sunitinib is an anti-cancer tyrosine kinase inhibitor associated with severe cardiotoxic adverse effects. Using rat Langendorff heart model and human acute myeloid leukemia 60 (HL60) cell line we detected the involvement of protein kinase C (PKC) α during Sunitinib-induced cardiotoxicity and the effect of Sunitinib on cancer progression. The cardioprotective and anti-cancer properties of the A3 adenosine receptor agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (IB-MECA) were investigated.
The cardiac effect of Sunitinib (1µM) and IB-MECA (1nM) treatment was measured through haemodynamic and infarct size assessment. The cytotoxic effect of Sunitinib (0.1 – 10 μM) and IB-MECA (10 nM – 10 μM) on HL60 cells was assessed using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay technique. Myocardial injury associated microRNAs (miR-1, miR-27a, miR-133a and miR-133b) and cancer associated microRNAs (miR-15a, miR-16-1 and miR-155) were profiled by qRT-PCR in the cardiac tissue and HL60 cells, while phosphorylated PKCα levels were measured by Western Blot analysis.
Sunitinib treatment increased infarct size and decreased left ventricular developed pressure and heart rate. Co-treatment of IB-MECA reversed the myocardial injury produced by Sunitinib administration. IB-MECA did not jeopardize the anti-cancer effect of Sunitinib in HL60 cells. The expression signature of the specific microRNAs in cardiac tissue and HL60 cells showed an altered expression profile when treated with Sunitinib and IB-MECA. pPKCα levels were increased by Sunitinib treatment in cardiac tissue and HL60 cells and co-administration of IB-MECA attenuated this increase in the cardiac tissue.
This study reveals that A3 adenosine receptor activation by IB-MECA attenuates Sunitinib-induced cardiotoxicity through the involvement of PKCα.

Publisher Statement: NOTICE: this is the author’s version of a work that was accepted for publication in European Journal of Pharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in European Journal of Pharmacology, [(in press), (2017)] DOI: 10.1016/j.ejphar.2017.08.011

© 2017, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Original languageEnglish
Pages (from-to)95-105
Number of pages11
JournalEuropean Journal of Pharmacology
Volume814
Early online date12 Aug 2017
DOIs
Publication statusPublished - 5 Nov 2017

Keywords

  • Rat Langendorff heart model
  • A3 adenosine receptor agonist IB-MECA
  • microRNAs
  • HL60 cell line
  • PKCα pathway
  • tyrosine kinase inhibitor Sunitinib

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

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