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PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With

Brent A McLean1,2, Vaibhav B Patel2,3, Pavel Zhabyeyev2,3

  • 11 Department of Physiology University of Alberta Edmonton Canada.

Journal of the American Heart Association
|May 2, 2019
PubMed

Insights

Cancer therapies targeting PI 3Kα (phosphoinositide 3-kinase-α) can harm the heart. This study found PI 3Kα inhibition combined with chemotherapy specifically risks right ventricular dilation and dysfunction.

Area of Science:

  • Cardiology
  • Oncology
  • Molecular Biology

Background:

  • Cancer therapies targeting PI 3Kα (phosphoinositide 3-kinase-α) signaling can cause cardiac adverse effects.
  • The impact of PI 3Kα pathway inhibition on heart health during cancer treatment remains unclear.

Purpose of the Study:

  • To investigate the effects of PI 3Kα pathway inhibition on heart atrophy, remodeling, and function.
  • To determine the specific cardiac risks associated with combined PI 3Kα inhibition and chemotherapy.

Main Methods:

  • Utilized pharmacological PI 3Kα inhibition and genetic deletion of p110α in murine models.
  • Administered anthracycline (doxorubicin) chemotherapy concurrently.
  • Analyzed biventricular morphology, function, and molecular signaling pathways.

Main Results:

  • Both PI 3Kα inhibition and doxorubicin promoted heart atrophy.
  • Combined therapy led to right ventricular dilation, dysfunction, and cardiomyocyte remodeling without pulmonary hypertension.
  • Increased p38 mitogen-activated protein kinase activation was linked to heart atrophy and right ventricular dysfunction.

Conclusions:

  • PI 3Kα pathway inhibition contributes to heart atrophy.
  • The right ventricle is particularly vulnerable to dilation and dysfunction when PI 3Kα inhibition is combined with chemotherapy.
  • Inhibiting p38 mitogen-activated protein kinase may mitigate this cardiotoxicity.
Keywords:
PI3Kanthracyclineheart atrophyremodelingright ventricle

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