Ageing alters the severity of Sunitinib-induced cardiotoxicity: Investigating the mitogen activated kinase kinase 7 pathway association

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

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Abstract

Anti-cancer drug Sunitinib is linked to adverse cardiovascular events, which have shown to involve mitogen activated kinase kinase 7 (MKK7) pathway. Sunitinib-induced cardiotoxicity in 3, 12 and 24 months old male Sprague-Dawley rats and MKK7 expression and activation was investigated using the Langendorff perfused heart model followed by Western blot analysis. Cardiac function and infarct size were measured during/after 125 min of Sunitinib treatment. Left ventricular cardiac samples were analysed by qRT-PCR for expression of MKK7 mRNA and cardiac injury associated microRNAs. Infarct size was increased in all Sunitinib treated age groups. Haemodynamic alterations were observed following Sunitinib administration. Left ventricular developed pressure (LVDP) was decreased in all age groups, while heart rate (HR) was decreased in 3 and 12 months groups. Sunitinib treatment decreased the expression of miR-27a in all age groups, while miR-133a and miR-133b levels were increased in 3 months and decreased in 24 months groups. MKK7 mRNA and p-MKK7 levels were decreased in the 3 months group after Sunitinib treatment. MKK7 mRNA level was increased in 24 months group and p-MKK7 levels were increased in 12 months group following Sunitinib treatment. This study highlights the importance and impact of ageing and anti-cancer therapy-induced cardiotoxicity.

Original languageEnglish
Pages (from-to)49-59
Number of pages11
JournalToxicology
Volume411
Early online date26 Oct 2018
DOIs
Publication statusPublished - 1 Jan 2019

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Mitogens
Phosphotransferases
Aging of materials
Association reactions
Age Groups
sunitinib
Cardiotoxicity
Messenger RNA
Therapeutics
Hemodynamics
Ventricular Pressure
MicroRNAs
Sprague Dawley Rats
Rats
Neoplasms
Heart Rate
Western Blotting
Chemical activation

Keywords

  • Anti-cancer therapy
  • Cardiac aging
  • Cardiotoxicity microRNAs
  • Mitogen activated kinase kinase 7
  • Sunitinib-induced cardiotoxicity

ASJC Scopus subject areas

  • Toxicology

Cite this

Ageing alters the severity of Sunitinib-induced cardiotoxicity: Investigating the mitogen activated kinase kinase 7 pathway association. / Cooper, Samantha; Sandhu, Hardip; Hussain, Afthab; Mee, Christopher; Maddock, Helen.

In: Toxicology, Vol. 411, 01.01.2019, p. 49-59.

Research output: Contribution to journalArticle

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