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January 18, 2018CirculationOpen Access

Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth

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Why the study?

Does PI3Kγ inhibition protect against doxorubicin-induced cardiotoxicity and reduce tumor growth in mouse models?

Population

Mice subjected to chronic doxorubicin (DOX) treatment, including mouse mammary tumor models.

Comparison

Genetic or pharmacological PI3Kγ inhibition. vs Wild-type mice or vehicle control (implied).

Design

Preclinical

Authors

MLMingchuan LiVSValentina SalaMSMaria Chiara De Santis

Discussion

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Overview

PI3Kγ inhibition preserved cardiac function in DOX-treated mice; leaves open translation to dual cardio-oncologic benefit in patients.

Key Points

  • Investigate the role of PI3Kγ in doxorubicin-induced cardiotoxicity and determine whether PI3Kγ inhibition provides cardioprotection while enhancing antitumor efficacy.
  • Treated mice expressing kinase-dead PI3Kγ or wild-type mice receiving PI3Kγ-selective inhibitors with chronic doxorubicin regimens.
  • Assessed cardiac function via echocardiography and mapped downstream autophagy and signaling pathways in whole hearts and isolated cardiomyocytes.
  • Evaluated dual cardioprotective and antitumor actions in mouse mammary tumor models.
  • Genetic inactivation or pharmacological inhibition of PI3Kγ preserved cardiac function by maintaining autophagic clearance of damaged mitochondria.
  • Doxorubicin injury released mitochondrial DNA that activated a TLR9-dependent PI3Kγ/Akt/mTOR/Ulk1 pathway, exerting maladaptive feedback inhibition on autophagy.
  • PI3Kγ blockade in mammary tumor models prevented heart dysfunction and synergized with doxorubicin to suppress tumor growth by stimulating anticancer immunity.

Structured PICO

Does PI3Kγ inhibition protect against doxorubicin-induced cardiotoxicity and reduce tumor growth in mouse models?

P
Population
Mice subjected to chronic doxorubicin (DOX) treatment, including mouse mammary tumor models.
I
Intervention
Genetic (kinase-inactive PI3Kγ) or pharmacological PI3Kγ inhibition.
C
Comparator
Wild-type mice or vehicle control (implied).
O
Outcome
Cardiac function (assessed by echocardiography) and tumor growth.surrogate

PI3Kγ inhibition may offer a dual therapeutic benefit in cancer therapy by preventing anthracycline-induced cardiotoxicity and enhancing antitumor efficacy.

Cite This Study

Li et al. (2018) studied this question.

synapsesocial.com/papers/6a73f703e3ef2a9a940ddcb0https://doi.org/10.1161/circulationaha.117.030352
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Phosphoinositide 3-Kinase γ–Deficient Mice Are Protected From Isoproterenol-Induced Heart Failure2003 · 161 citations
  2. 2Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience.1997 · 480 citations
  3. 3Distinct Effects of Leukocyte and Cardiac Phosphoinositide 3-Kinase γ Activity in Pressure Overload–Induced Cardiac Failure2011 · 73 citations
  4. 4Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation2014 · 897 citations
  5. 5Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection2012 · 329 citations