title: Doxorubicin-induced chronic dilated cardiomyopathy-the apoptosis hypothesis revisited.
abstract: The chemotherapeutic agent doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10% of pediatric cancer survivors will 10-20 years later develop severe dilated cardiomyopathy (DCM), whereby the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidence, we first argue why a dilated phenotype can occur when little apoptosis is detected. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream of mitochondrial outer membrane permeabilisation (MOMP). This lack of MOMP induction is proposed to alter the metabolic phenotype, induce hypertrophic remodeling, and lead to functional cardiac impairment even in the absence of cardiomyocyte apoptosis. We discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosis-primed cancer cells and propose computational system biology as a tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM.
authors.affiliation: Department of Cardiovascular Sciences, KU Leuven, 3000, Leuven, Belgium.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Kankeu
authors.affiliation: Department of Cardiovascular Sciences, KU Leuven, 3000, Leuven, Belgium.
authors.forename: Kylie
authors.initials: K
authors.lastname: Clarke
authors.affiliation: School of Pharmacy and Biomedical Sciences, Univ. of Central Lancashire, Preston, UK.
authors.forename: Egle
authors.initials: E
authors.lastname: Passante
authors.affiliation: Department of Cardiovascular Sciences, KU Leuven, 3000, Leuven, Belgium. heinhuber@rcsi.ie.|Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland. heinhuber@rcsi.ie.
authors.forename: Heinrich J
authors.initials: HJ
authors.lastname: Huber
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D004317:Doxorubicin / Q000009:adverse effects*; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin
keywords: Apoptosis; Dilated cardiomyopathy (DCM); Doxorubicin (DOX); Systems biology