title: Doxorubicin induces senescence and impairs function of human cardiac progenitor cells.
abstract: The increasing population of cancer survivors faces considerable morbidity and mortality due to late effects of the antineoplastic therapy. Cardiotoxicity is a major limiting factor of therapy with doxorubicin (DOXO), the most effective anthracycline, and is characterized by a dilated cardiomyopathy that can develop even years after treatment. Studies in animals have proposed the cardiac progenitor cells (CPCs) as the cellular target responsible for DOXO-induced cardiomyopathy but the relevance of these observations to clinical settings is unknown. In this study, the analysis of the DOXO-induced cardiomyopathic human hearts showed that the majority of human CPCs (hCPCs) was senescent. In isolated hCPCs, DOXO triggered DNA damage response leading to apoptosis early after exposure, and telomere shortening and senescence at later time interval. Functional properties of hCPCs, such as migration and differentiation, were also negatively affected. Importantly, the differentiated progeny of DOXO-treated hCPCs prematurely expressed the senescence marker p16(INK4a). In conclusion, DOXO exposure severely affects the population of hCPCs and permanently impairs their function. Premature senescence of hCPCs and their progeny can be responsible for the decline in the regenerative capacity of the heart and may represent the cellular basis of DOXO-induced cardiomyopathy in humans.
authors: Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Naples, Italy. elena.piegari@unina2.it
authors: Elena
authors: E
authors: Piegari
authors: Antonella
authors: A
authors: De Angelis
authors: Donato
authors: D
authors: Cappetta
authors: Rosa
authors: R
authors: Russo
authors: Grazia
authors: G
authors: Esposito
authors: Sarah
authors: S
authors: Costantino
authors: Gallia
authors: G
authors: Graiani
authors: Caterina
authors: C
authors: Frati
authors: Lucia
authors: L
authors: Prezioso
authors: Liberato
authors: L
authors: Berrino
authors: Konrad
authors: K
authors: Urbanek
authors: Federico
authors: F
authors: Quaini
authors: Francesco
authors: F
authors: Rossi
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008297:Male; D008875:Middle Aged; D032386:Myoblasts, Cardiac / Q000187:drug effects*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects*; D059505:Telomere Homeostasis; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D019009:Proto-Oncogene Proteins c-kit; D001616:beta-Galactosidase