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

Mingchuan Li, Valentina Sala, Maria Chiara De Santis, James Cimino, Paola Cappello, Nicola Pianca, Anna Di Bona, Jean Piero Margaria, Miriam Martini, Edoardo Lazzarini, Flora Pirozzi, Luca Rossi, Irene Franco, Julia Bornbaum, Jacqueline Heger, Susanne Rohrbach, Alessia Perino, Carlo G. Tocchetti, Braulio H.F. Lima, Mauro M. TeixeiraPaolo E. Porporato, Rainer Schulz, Annalisa Angelini, Marco Sandri, Pietro Ameri, Sebastiano Sciarretta, Roberto César P. Lima-Júnior, Marco Mongillo, Tania Zaglia, Fulvio Morello, Francesco Novelli, Emilio Hirsch, Alessandra Ghigo

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)696-711
Number of pages16
JournalCirculation
Volume138
Issue number7
DOIs
Publication statusPublished - Aug 14 2018

Keywords

  • anthracyclines
  • autophagy
  • cardiotoxicity
  • immunosuppression
  • PI3Kγ

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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