| First Author | Li M | Year | 2018 |
| Journal | Circulation | Volume | 138 |
| Issue | 7 | Pages | 696-711 |
| PubMed ID | 29348263 | Mgi Jnum | J:287824 |
| Mgi Id | MGI:6363912 | Doi | 10.1161/CIRCULATIONAHA.117.030352 |
| Citation | Li M, et al. (2018) Phosphoinositide 3-Kinase Gamma Inhibition Protects From Anthracycline Cardiotoxicity and Reduces Tumor Growth. Circulation 138(7):696-711 |
| abstractText | 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 gamma (PI3Kgamma) in DOX-induced cardiotoxicity and the potential cardioprotective and anticancer effects of PI3Kgamma inhibition. METHODS: Mice expressing a kinase-inactive PI3Kgamma or receiving PI3Kgamma-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 PI3Kgamma inhibition was assessed in mouse mammary tumor models. RESULTS: PI3Kgamma kinase-dead mice showed preserved cardiac function after chronic low-dose DOX treatment and were protected against DOX-induced cardiotoxicity. The beneficial effects of PI3Kgamma 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 PI3Kgamma kinase-dead mice to DOX cardiotoxicity. Mechanistically, PI3Kgamma 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 PI3Kgamma/Akt/mTOR/Ulk1 signaling provided maladaptive feedback inhibition of autophagy. PI3Kgamma 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 PI3Kgamma may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth. |
