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

Circulation. 2018 Aug 14;138(7):696-711. doi: 10.1161/CIRCULATIONAHA.117.030352.


Background: Anthracyclines, such as doxorubicin (DOX), are potent anticancer agents for the treatment of solid tumors and hematologic malignancies. However, their clinical use is hampered by cardiotoxicity. This study sought to investigate the role of phosphoinositide 3-kinase γ (PI3Kγ) in DOX-induced cardiotoxicity and the potential cardioprotective and anticancer effects of PI3Kγ inhibition.

Methods: Mice expressing a kinase-inactive PI3Kγ or receiving PI3Kγ-selective inhibitors were subjected to chronic DOX treatment. Cardiac function was analyzed by echocardiography, and DOX-mediated signaling was assessed in whole hearts or isolated cardiomyocytes. The dual cardioprotective and antitumor action of PI3Kγ inhibition was assessed in mouse mammary tumor models.

Results: PI3Kγ kinase-dead mice showed preserved cardiac function after chronic low-dose DOX treatment and were protected against DOX-induced cardiotoxicity. The beneficial effects of PI3Kγ inhibition were causally linked to enhanced autophagic disposal of DOX-damaged mitochondria. Consistently, either pharmacological or genetic blockade of autophagy in vivo abrogated the resistance of PI3Kγ kinase-dead mice to DOX cardiotoxicity. Mechanistically, PI3Kγ was triggered in DOX-treated hearts, downstream of Toll-like receptor 9, by the mitochondrial DNA released by injured organelles and contained in autolysosomes. This autolysosomal PI3Kγ/Akt/mTOR/Ulk1 signaling provided maladaptive feedback inhibition of autophagy. PI3Kγ blockade in models of mammary gland tumors prevented DOX-induced cardiac dysfunction and concomitantly synergized with the antitumor action of DOX by unleashing anticancer immunity.

Conclusions: Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.

Keywords: PI3Kγ; anthracyclines; autophagy; cardiotoxicity; immunosuppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Antibiotics, Antineoplastic / toxicity
  • Autophagy / drug effects*
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cardiotoxicity
  • Class Ib Phosphatidylinositol 3-Kinase / genetics
  • Class Ib Phosphatidylinositol 3-Kinase / metabolism
  • Cytoprotection
  • Disease Models, Animal
  • Doxorubicin / pharmacology*
  • Doxorubicin / toxicity
  • Female
  • Genes, erbB-2
  • Heart Diseases / chemically induced
  • Heart Diseases / enzymology
  • Heart Diseases / pathology
  • Heart Diseases / prevention & control*
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Mutation
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / pathology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / pharmacology*
  • Quinoxalines / pharmacology*
  • Thiazolidinediones / pharmacology*
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / metabolism
  • Tumor Burden / drug effects*


  • 5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
  • Antibiotics, Antineoplastic
  • Autophagy-Related Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Quinoxalines
  • Thiazolidinediones
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Doxorubicin
  • Class Ib Phosphatidylinositol 3-Kinase
  • Pik3cg protein, mouse