title: Metformin protects cardiomyocyte from doxorubicin induced cytotoxicity through an AMP-activated protein kinase dependent signaling pathway: an in vitro study.
abstract: Doxorubicin (Dox) is one of the most widely used antitumor drugs, but its cumulative cardiotoxicity have been major concerns in cancer therapeutic practice for decades. Recent studies established that metformin (Met), an oral anti-diabetic drug, provides protective effects in Dox-induced cardiotoxicity. Met has been shown to increase fatty acid oxidation, an effect mediated by AMP activated protein kinase (AMPK). Here we delineate the intracellular signaling factors involved in Met mediated protection against Dox-induced cardiotoxicity in the H9c2 cardiomyoblast cell line. Treatment with low dose Met (0.1 mM) increased cell viabilities and Ki-67 expressions while decreasing LDH leakages, ROS generations and [Ca2+]i. The protective effect was reversed by a co-treatment with compound-C, an AMPK specific inhibitor, or by an over expression of a dominant-negative AMPKα cDNA. Inhibition of PKA with H89 or a suppression of Src kinase by a small hairpin siRNA also abrogated the protective effect of the low dose Met. Whereas, with a higher dose of Met (1.0 mM), the protective effects were abolished regardless of the enhanced AMPK, PKA/CREB1 and Src kinase activity. In high dose Met treated cells, expression of platelet-derived growth factor receptor (PDGFR) was significantly suppressed. Furthermore, the protective effect of low dose Met was totally reversed by co-treatment with AG1296, a PDGFR specific antagonist. These data provide in vitro evidence supporting a signaling cascade by which low dose Met exerts protective effects against Dox via sequential involvement of AMPK, PKA/CREB1, Src and PDGFR. Whereas high dose Met reverses the effect by suppressing PDGFR expression.
authors.affiliation: Department of Pediatrics, Women & Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Kobashigawa
authors.affiliation: Department of Pediatrics, Women & Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Yan Chun
authors.initials: YC
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Women & Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: James F
authors.initials: JF
authors.lastname: Padbury
authors.affiliation: Department of Pediatrics, Women & Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Yi-Tang
authors.initials: YT
authors.lastname: Tseng
authors.affiliation: Department of Pediatrics, Women & Infants Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Yano
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D066126:Cardiotoxicity; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D004789:Enzyme Activation; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D008687:Metformin; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases