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Doxorubicin induces senescence and impairs function of human cardiac progenitor cells

  • Elena Piegari
  • Antonella De AngelisEmail author
  • Donato Cappetta
  • Rosa Russo
  • Grazia Esposito
  • Sarah Costantino
  • Gallia Graiani
  • Caterina Frati
  • Lucia Prezioso
  • Liberato Berrino
  • Konrad Urbanek
  • Federico Quaini
  • Francesco Rossi
Original Contribution

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.

Keywords

Cardiotoxicity Doxorubicin Cardiac progenitor cells Senescence 

Notes

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).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (PDF 901 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Elena Piegari
    • 1
    • 2
  • Antonella De Angelis
    • 1
    • 2
    Email author
  • Donato Cappetta
    • 1
    • 2
  • Rosa Russo
    • 1
    • 2
  • Grazia Esposito
    • 1
    • 2
  • Sarah Costantino
    • 1
    • 2
  • Gallia Graiani
    • 3
  • Caterina Frati
    • 3
  • Lucia Prezioso
    • 3
  • Liberato Berrino
    • 1
    • 2
  • Konrad Urbanek
    • 1
    • 2
  • Federico Quaini
    • 3
  • Francesco Rossi
    • 1
    • 2
  1. 1.Department of Experimental Medicine, Section of PharmacologySecond University of NaplesNaplesItaly
  2. 2.Excellence Research Center for Cardiovascular Diseases, Department of Experimental MedicineSecond University of NaplesNaplesItaly
  3. 3.Departments of Medicine and PathologyUniversity of ParmaParmaItaly

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