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

Hardip Sandhu1, Samantha Cooper1, Afthab Hussain1

  • 1Faculty Research Centre in Applied Biological and Exercise Sciences, Faculty of Health and Life Sciences, Coventry University, United Kingdom.

European Journal of Pharmacology
|August 17, 2017
PubMed

Insights

The A3 adenosine receptor agonist IB-MECA protects against Sunitinib-induced cardiotoxicity by inhibiting protein kinase C alpha (PKCα) activation. IB-MECA preserves Sunitinib

Area of Science:

  • Pharmacology and Toxicology
  • Cardiovascular Research
  • Oncology

Background:

  • Sunitinib, an anti-cancer tyrosine kinase inhibitor, is linked to severe cardiotoxic effects.
  • Protein kinase C alpha (PKCα) involvement in Sunitinib-induced cardiotoxicity and cancer progression requires further investigation.
  • The A3 adenosine receptor agonist IB-MECA exhibits potential cardioprotective and anti-cancer properties.

Purpose of the Study:

  • To investigate the cardioprotective and anti-cancer effects of IB-MECA in the context of Sunitinib treatment.
  • To elucidate the role of protein kinase C alpha (PKCα) in Sunitinib-induced cardiotoxicity.
  • To assess the impact of IB-MECA on Sunitinib's anti-cancer efficacy.

Main Methods:

  • Utilized a rat Langendorff heart model and human acute myeloid leukemia (HL60) cell line.
  • Assessed cardiac function (hemodynamics, infarct size) and HL60 cell cytotoxicity (MTT assay).
  • Profiled myocardial and cancer-associated microRNAs (qRT-PCR) and measured phosphorylated PKCα levels (Western Blot).

Main Results:

  • Sunitinib increased cardiac infarct size and decreased left ventricular pressure and heart rate.
  • IB-MECA co-treatment reversed Sunitinib-induced myocardial injury without compromising its anti-cancer effect on HL60 cells.
  • Sunitinib elevated phosphorylated PKCα levels in cardiac tissue and HL60 cells; IB-MECA attenuated this increase in cardiac tissue.

Conclusions:

  • Activation of the A3 adenosine receptor by IB-MECA attenuates Sunitinib-induced cardiotoxicity.
  • The cardioprotective mechanism involves the modulation of protein kinase C alpha (PKCα) signaling.
  • IB-MECA offers a potential therapeutic strategy to mitigate Sunitinib's cardiac side effects.
Keywords:
A(3) adenosine receptor agonist IB-MECAHL60 cell lineMicroRNAsPKCα pathwayRat Langendorff heart modelTyrosine kinase inhibitor Sunitinib

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