Phosphoinositide 3-Kinase Gamma Inhibition Protects from Anthracycline Cardiotoxicity and Reduces Tumor Growth
| Autor: | Susanne Rohrbach, Mauro M. Teixeira, Flora Pirozzi, Miriam Martini, Irene Franco, Alessia Perino, Jean Piero Margaria, Roberto C. P. Lima-Júnior, Jacqueline Heger, Annalisa Angelini, Valentina Sala, Francesco Novelli, Alessandra Ghigo, Maria Chiara De Santis, Marco Mongillo, Anna Di Bona, Mingchuan Li, Julia Bornbaum, Carlo G. Tocchetti, Sebastiano Sciarretta, Emilio Hirsch, Tania Zaglia, Luca Rossi, Paolo E. Porporato, Pietro Ameri, Paola Cappello, Rainer Schulz, Fulvio Morello, Edoardo Lazzarini, Braulio H.F. Lima, Marco Sandri, James Cimino, Nicola Pianca |
|---|---|
| Přispěvatelé: | Li, Mingchuan, Sala, Valentina, De Santis, Maria Chiara, Cimino, Jame, Cappello, Paola, Pianca, Nicola, Di Bona, Anna, Margaria, Jean Piero, Martini, Miriam, Lazzarini, Edoardo, Pirozzi, Flora, Rossi, Luca, Franco, Irene, Bornbaum, Julia, Heger, Jacqueline, Rohrbach, Susanne, Perino, Alessia, Tocchetti, Carlo G, Lima, Braulio H F, Teixeira, Mauro M, Porporato, Paolo E, Schulz, Rainer, Angelini, Annalisa, Sandri, Marco, Ameri, Pietro, Sciarretta, Sebastiano, Lima-Júnior, Roberto César P, Mongillo, Marco, Zaglia, Tania, Morello, Fulvio, Novelli, Francesco, Hirsch, Emilio, Ghigo, Alessandra |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment inbred balb c Autophagy-Related Proteins Anthracycline 030204 cardiovascular system & hematology antibiotics PI3Kγ 0302 clinical medicine Class Ib Phosphatidylinositol 3-Kinase animal Myocytes Cardiac Anthracyclines genes Phosphoinositide-3 Kinase Inhibitors Mice Inbred BALB C Antibiotics Antineoplastic immunosuppression biology Immunosuppression Tumor Burden Female Cardiology and Cardiovascular Medicine medicine.drug autophagy mice Heart Diseases antineoplastic cardiac cardiotoxicity Anthracyclines PI3Kγ autophagy cardiotoxicity immunosuppression Breast Neoplasms Mice Transgenic 03 medical and health sciences cardiotoxicityb Physiology (medical) Quinoxalines medicine Animals Doxorubicin Tumor growth Protein Kinase Inhibitors transgenic Cardiotoxicity disease models Phosphoinositide 3-kinase business.industry Autophagy myocytes Genes erbB-2 Disease Models Animal 030104 developmental biology Cytoprotection Toll-Like Receptor 9 Mutation biology.protein Cancer research Thiazolidinediones anthracyclines pi3kγ animals antibiotics antineoplastic autophagy-related proteins breast neoplasms class ib phosphatidylinositol 3-kinase cytoprotection disease models animal doxorubicin female genes erbb-2 heart diseases mice inbred balb c mice transgenic mutation myocytes cardiac protein kinase inhibitors quinoxalines thiazolidinediones toll-like receptor 9 tumor burden phosphoinositide-3 kinase inhibitors business erbb-2 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|