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Single nanomolar doxorubicin exposure triggers compensatory mitochondrial responses in H9c2 cardiomyoblasts

Luciana L Ferreira1, Teresa Cunha-Oliveira1, Caroline D Veloso1

  • 1CNC - Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech Building, Biocant Park, 3060-197, Cantanhede, Portugal.

Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association
|December 18, 2018
PubMed

Insights

Low-dose doxorubicin (DOX) pretreatment may protect heart cells from damage. This study found that nanomolar DOX induced mitochondrial adaptations and increased resistance to subsequent DOX exposure in H9c2 cardiomyoblasts.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Doxorubicin (DOX) causes dose-dependent cardiotoxicity, limiting its use in cancer therapy.
  • Pediatric cancer survivors face persistent risks, with no current prevention strategies.
  • Understanding sub-therapeutic DOX effects on heart cells is crucial for developing protective measures.

Purpose of the Study:

  • Investigate persistent effects of nanomolar DOX on H9c2 cardiomyoblasts.
  • Determine if DOX pretreatment induces protective mitochondrial adaptations.
  • Explore potential epigenetic mechanisms underlying DOX-induced protection.

Main Methods:

  • H9c2 cardiomyoblasts were incubated with 10 and 25 nM DOX for 24 hours, followed by 9 days of recovery.
  • Assessed cell hypertrophy, cell cycle progression, glycolytic activity, and mitochondrial respiration.
  • Analyzed mitochondrial DNA transcripts, DNA methyltransferase 1 (DNMT1) levels, and global methylation.

Main Results:

  • Sub-therapeutic DOX induced persistent hypertrophy and G2/M cell cycle arrest.
  • Decreased glycolytic activity and basal respiration were observed, with similar maximal respiration.
  • DOX pretreatment upregulated mitochondrial DNA transcripts and decreased DNMT1 and global methylation.
  • Pretreated cells showed enhanced resistance to subsequent DOX exposure.

Conclusions:

  • Nanomolar DOX pretreatment induces beneficial mitochondrial adaptations in H9c2 cardiomyoblasts.
  • These adaptations may be epigenetically mediated, involving changes in DNA methylation.
  • Early sub-therapeutic DOX exposure could serve as a preconditioning strategy to protect against DOX cardiotoxicity.
Keywords:
CardiotoxicityDNA methylationDoxorubicinH9c2 cellsMitochondria

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