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Doxorubicin induces senescence and impairs function of human cardiac progenitor cells

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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 p16INK4a. 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.

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Acknowledgments

This work was supported by Grants from the Italian Ministry of Education, (PRIN 2007: 2007AL2YNC_004, PRIN 2007: 2007AL2YNC_001), the Italian Ministry of Health (THEAPPL 2008) and the European Commission CORDIS(FP7-BIOSCENT, NMP-214539 2007).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Experimental Medicine, Section of Pharmacology, Second University of Naples, Via Costantinopoli 16, 80138, Naples, Italy

    Elena Piegari, Antonella De Angelis, Donato Cappetta, Rosa Russo, Grazia Esposito, Sarah Costantino, Liberato Berrino, Konrad Urbanek & Francesco Rossi

  2. Excellence Research Center for Cardiovascular Diseases, Department of Experimental Medicine, Second University of Naples, Naples, Italy

    Elena Piegari, Antonella De Angelis, Donato Cappetta, Rosa Russo, Grazia Esposito, Sarah Costantino, Liberato Berrino, Konrad Urbanek & Francesco Rossi

  3. Departments of Medicine and Pathology, University of Parma, Via Gramsci 14, Parma, Italy

    Gallia Graiani, Caterina Frati, Lucia Prezioso & Federico Quaini

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  1. Elena Piegari
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  2. Antonella De Angelis
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Correspondence to Antonella De Angelis.

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E. Piegari and A. De Angelis are contributed equally to this work.

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Piegari, E., De Angelis, A., Cappetta, D. et al. Doxorubicin induces senescence and impairs function of human cardiac progenitor cells. Basic Res Cardiol 108, 334 (2013). https://doi.org/10.1007/s00395-013-0334-4

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