Basal autophagy protects cardiomyocytes from doxorubicin-induced toxicity.
Doxorubicin (Doxo) is one of the most effective anti-neoplastic agents but its cardiotoxicity has been an important clinical limitation. The major mechanism of Doxo-induced cardiotoxicity is associated to its oxidative capacity. However, other processes are also involved with significant consequences for the cardiomyocyte. In recent years, a number of studies have investigated the role of autophagy on Doxo-induced cardiotoxicity but to date it is not clear how Doxo alters that process and its consequence on cardiomyocytes viability. Here we investigated the effect of Doxo 1uM for 24h of stimulation on cultured neonatal rat cardiomyocytes. We showed that Doxo inhibits basal autophagy. This inhibition is due to both Akt/mTOR signaling pathway activation and Beclin 1 level decrease. To assess the role of autophagy on Doxo-induced cardiomyocyte death, we evaluated the effects 3-methyladenine (3-MA), bafilomycin A1 (BafA), siRNA Beclin 1 (siBeclin 1) and rapamycin (Rapa) on cell viability. Inhibition of autophagy with 3-MA, BafA and siBeclin 1 increased lactate dehydrogenase (LDH) release but, when autophagy was induced by Rapa, Doxo-induced cardiomyocyte death was decreased. These results suggest that Doxo inhibits basal autophagy and contributes to cardiomyocyte death. Activation of autophagy could be used as a strategy to protect the heart against Doxo toxicity.
Advanced Center for Chronic Disease (ACCDiS) & Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Marcela
M
Pizarro
Advanced Center for Chronic Disease (ACCDiS) & Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile.
Rodrigo
R
Troncoso
Advanced Center for Chronic Disease (ACCDiS), Unidad de Cardio-Oncología, División Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Gonzalo J
GJ
Martínez
Advanced Center for Chronic Disease (ACCDiS) & Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Mario
M
Chiong
Advanced Center for Chronic Disease (ACCDiS), Unidad de Cardio-Oncología, División Enfermedades Cardiovasculares, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Pablo F
PF
Castro
Advanced Center for Chronic Disease (ACCDiS) & Center for Molecular Studies of the Cell (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: sergiolavandero@gmail.com.
Sergio
S
Lavandero
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D000071186:Beclin-1 / Q000235:genetics / Q000378:metabolism; D054715:Cardiotoxins / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D000225:Adenine; D000903:Antibiotics, Antineoplastic; D000071186:Beclin-1; D054715:Cardiotoxins; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C526109:Anxa3 protein, rat; C025946:3-methyladenine; C040929:bafilomycin A1; C546845:mTOR protein, rat
Autophagy; Cardiomyocyte; Doxorubicin