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Sodium-glucose cotransporter type 2 inhibitors prevent ponatinib-induced endothelial senescence and disfunction: A

Rosalinda Madonna1, Serena Barachini2, Stefania Moscato3

  • 1Department of Pathology, Cardiology Division, University of Pisa, Pisa, Italy.

Vascular Pharmacology
|November 29, 2021
PubMed
Abstract

Insights

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors like empagliflozin and dapagliflozin protect against ponatinib-induced vascular toxicity. These SGLT2 inhibitors reverse endothelial cell senescence and dysfunction, suggesting potential clinical applications.

Area of Science:

  • Cardiovascular Pharmacology
  • Endothelial Cell Biology
  • Drug-Induced Toxicity Mechanisms

Background:

  • Ponatinib (PON), a third-generation tyrosine kinase inhibitor (TKI), exhibits significant cardiovascular toxicity.
  • Currently, no established agents can prevent PON-induced cardiovascular side effects.
  • Sodium-glucose cotransporter type 2 (SGLT2) inhibitors demonstrate promising cardiac and vascular protective properties.

Purpose of the Study:

  • To evaluate the protective effects of SGLT2 inhibitors empagliflozin (EMPA) and dapagliflozin (DAPA) against ponatinib (PON)-induced endothelial toxicity.
  • To investigate the underlying vasculo-protective mechanisms in an in vitro model using human aortic endothelial cells (HAECs).

Main Methods:

  • Human aortic endothelial cells (HAECs) were exposed to PON or vehicle (DMSO) with or without EMPA or DAPA.
  • Cell viability, senescence, autophagy, and tubulization capacity were assessed over 0-48 hours.
  • Quantitative assays included β-galactosidase staining, Matrigel assays, immunofluorescence, and flow cytometry.

Main Results:

  • PON significantly reduced HAEC viability, increased senescence, and decreased tubulization compared to vehicle controls.
  • EMPA and DAPA treatment reversed PON-induced reductions in cell viability and tubulization.
  • EMPA and DAPA also attenuated PON-induced endothelial cell senescence and promoted autophagy.

Conclusions:

  • Empagliflozin and dapagliflozin mitigate the vascular toxicity of ponatinib by reversing endothelial cell senescence and dysfunction.
  • These findings support further clinical investigation into the vasculo-protective potential of SGLT2 inhibitors in patients treated with ponatinib.
Keywords:
AutophagyPonatinibSodium-glucose cotransporter type 2 (SGLT2) inhibitorsTyrosine kinase inhibitorsVascular toxicity

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