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Involvement of mitogen activated kinase kinase 7 intracellular signalling pathway in Sunitinib-induced cardiotoxicity

Samantha Louise Cooper1, Hardip Sandhu1, Afthab Hussain1

  • 1Faculty Research Centre for Sport, Exercise and Life Sciences, Faculty of Health and Life Sciences, Science & Health Building, 20 Whitefriars Street, Coventry, CV1 2DS, United Kingdom.

Toxicology
|December 18, 2017
PubMed

Insights

Sunitinib cancer drug causes heart damage by inhibiting the ASK1/MKK7/JNK pathway. Blocking this pathway with NQDI-1 protects the heart and enhances Sunitinib's anti-cancer effects.

Area of Science:

  • Cardiovascular Research
  • Oncology
  • Molecular Biology

Background:

  • Sunitinib, a tyrosine kinase inhibitor used in cancer treatment, is associated with severe cardiovascular adverse events.
  • The mitogen-activated kinase kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK) pathway are implicated in cardiac injury.
  • Apoptosis signal-regulating kinase 1 (ASK1) is an upstream activator of MKK7, and its inhibitor is NQDI-1.

Purpose of the Study:

  • To investigate the role of the ASK1/MKK7/JNK signaling pathway in Sunitinib-induced cardiotoxicity.
  • To evaluate the cardioprotective effects of NQDI-1 against Sunitinib-induced cardiac injury.
  • To assess the impact of NQDI-1 on Sunitinib's anti-cancer efficacy.

Main Methods:

  • Isolated male Sprague-Dawley rat Langendorff perfused hearts were treated with Sunitinib with or without NQDI-1.
  • Cardiac tissue was analyzed for MKK7 mRNA expression and cardiotoxicity-associated microRNAs (miR-1, miR-27a, miR-133a, miR-133b) via qRT-PCR.
  • Western blot analysis was performed to measure ASK1/MKK7/JNK phosphorylation.
  • Human acute myeloid leukemia 60 (HL60) cell line viability was assessed using the MTT assay.

Main Results:

  • Sunitinib administration increased infarct size and miR-133a expression while decreasing ASK1/MKK7/JNK phosphorylation.
  • Co-administration of NQDI-1 attenuated Sunitinib-induced infarct size, reversed miR-133a expression, and restored ASK1/MKK7/JNK phosphorylation.
  • Sunitinib reduced HL60 cell viability, and this effect was enhanced by NQDI-1.

Conclusions:

  • The ASK1/MKK7/JNK intracellular signaling pathway plays a significant role in Sunitinib-induced cardiotoxicity.
  • NQDI-1 demonstrates cardioprotective effects against Sunitinib-induced cardiac injury.
  • Targeting the ASK1/MKK7/JNK pathway may offer a strategy for developing adjunct therapies to prevent Sunitinib-related cardiotoxicity and enhance anti-cancer outcomes.
Keywords:
ASK1 inhibitor 2,7-dihydro-2,7-dioxo-3H-naphtho[1,2,3-de]quinoline-1-carboxylic acid ethyl esterDrug-induced cardiotoxicityMitogen activated kinase kinase 7Novel adjunct therapySunitinibTyrosine kinase inhibitor

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