TY - JOUR
T1 - Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth
AU - Li, Mingchuan
AU - Sala, Valentina
AU - De Santis, Maria Chiara
AU - Cimino, James
AU - Cappello, Paola
AU - Pianca, Nicola
AU - Di Bona, Anna
AU - Margaria, Jean Piero
AU - Martini, Miriam
AU - Lazzarini, Edoardo
AU - Pirozzi, Flora
AU - Rossi, Luca
AU - Franco, Irene
AU - Bornbaum, Julia
AU - Heger, Jacqueline
AU - Rohrbach, Susanne
AU - Perino, Alessia
AU - Tocchetti, Carlo G.
AU - Lima, Braulio H.F.
AU - Teixeira, Mauro M.
AU - Porporato, Paolo E.
AU - Schulz, Rainer
AU - Angelini, Annalisa
AU - Sandri, Marco
AU - Ameri, Pietro
AU - Sciarretta, Sebastiano
AU - Lima-Júnior, Roberto César P.
AU - Mongillo, Marco
AU - Zaglia, Tania
AU - Morello, Fulvio
AU - Novelli, Francesco
AU - Hirsch, Emilio
AU - Ghigo, Alessandra
PY - 2018/8/14
Y1 - 2018/8/14
N2 - 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.
AB - 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.
KW - anthracyclines
KW - autophagy
KW - cardiotoxicity
KW - immunosuppression
KW - PI3Kγ
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UR - http://www.scopus.com/inward/citedby.url?scp=85044905006&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.117.030352
DO - 10.1161/CIRCULATIONAHA.117.030352
M3 - Article
C2 - 29348263
AN - SCOPUS:85044905006
VL - 138
SP - 696
EP - 711
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 7
ER -