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Phenotypic profiling of structural cardiotoxins in vitro reveals dependency on multiple mechanisms of toxicity

Amy Pointon1, Najah Abi-Gerges, Michael J Cross

  • 1Molecular Toxicology, Global Safety Assessment UK, Innovative Medicines, AstraZeneca R&D, Macclesfield, SK10 4TG, UK. amy.pointon@astrazeneca.com

Toxicological Sciences : an Official Journal of the Society of Toxicology
|January 15, 2013
PubMed

Insights

Developing new methods to predict drug-induced structural cardiotoxicity is crucial. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) provide a powerful in vitro model for early detection and mechanistic insights in drug development.

Area of Science:

  • Cardiovascular Research
  • Drug Development
  • Toxicology

Background:

  • Structural cardiotoxicity, leading to cardiomyocyte damage or death, is a major hurdle in drug development.
  • Current in vitro methods lack predictive power for early detection of this liability.
  • Understanding the mechanisms of structural cardiotoxicity remains limited.

Purpose of the Study:

  • To develop and validate an in vitro assay using human embryonic stem cell-derived cardiomyocytes (hESC-CMs) for predicting structural cardiotoxicity.
  • To compare the efficacy of hESC-CMs with rat H9c2 cells in detecting cardiotoxicity at therapeutically relevant concentrations.
  • To elucidate the underlying mechanisms of structural cardiotoxicity.

Main Methods:

  • Phenotypic profiling of cardiotoxins using live-cell fluorescent imaging in hESC-CMs and H9c2 cells.
  • Assays included mitochondrial membrane potential, endoplasmic reticulum integrity, Ca(2+) mobilization, membrane permeability, and cell viability (ATP depletion).
  • Results were normalized to therapeutically relevant concentrations, and findings were correlated with known in vivo effects.

Main Results:

  • hESC-CMs demonstrated superior performance over H9c2 cells in detecting structural cardiotoxicity at relevant concentrations.
  • Inhibition of spontaneous beating in hESC-CMs conferred cardioprotection against 10 of 13 cardiotoxins, highlighting the function-structure relationship.
  • Mitochondria and calcium mobilization were identified as key targets, with limited impact on contractile function in canine cardiomyocytes.

Conclusions:

  • hESC-CMs are a valuable tool for early identification of structural cardiotoxicity hazards during drug development.
  • The study provides insights into the complex mechanisms driving structural cardiotoxicity.
  • This approach aids in mitigating drug attrition due to cardiotoxicity.

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