Doxorubicin persistently rewires cardiac circadian homeostasis in mice

Research output: Contribution to journalArticle


  • Luciana L. Ferreira
  • Marlene Cervantes
  • Hugo J.C. Froufe
  • Conceição Egas
  • Teresa Cunha-Oliveira
  • Paolo Sassone-Corsi
  • Paulo J. Oliveira

External Institution(s)

  • University of Coimbra
  • Next Generation Sequencing Unit
  • University of California at Irvine
  • University of Coimbra


Original languageEnglish (US)
Pages (from-to)257-271
Number of pages15
JournalArchives of Toxicology
Issue number1
StatusPublished - Jan 1 2020


Circadian rhythms disruption can be the cause of chronic diseases. External cues, including therapeutic drugs, have been shown to modulate peripheral-circadian clocks. Since anthracycline cardiotoxicity is associated with loss of mitochondrial function and metabolic remodeling, we investigated whether the energetic failure induced by sub-chronic doxorubicin (DOX) treatment in juvenile mice was associated with persistent disruption of circadian regulators. Juvenile C57BL/6J male mice were subjected to a sub-chronic DOX treatment (4 weekly injections of 5 mg/kg DOX) and several cardiac parameters, as well as circadian-gene expression and acetylation patterns, were analyzed after 6 weeks of recovery time. Complementary experiments were performed with Mouse Embryonic Fibroblasts (MEFs) and Human Embryonic Kidney 293 cells. DOX-treated juvenile mice showed cardiotoxicity markers and persistent alterations of transcriptional- and signaling cardiac circadian homeostasis. The results showed a delayed influence of DOX on gene expression, accompanied by changes in SIRT1-mediated cyclic deacetylation. The mechanism behind DOX interference with the circadian clock was further studied in vitro, in which were observed alterations of circadian-gene expression and increased BMAL1 SIRT1-mediated deacetylation. In conclusion, DOX treatment in juvenile mice resulted in disruption of oscillatory molecular mechanisms including gene expression and acetylation profiles.

    Research areas

  • Cardiotoxicity, Chemotherapy, Circadian clock, Doxorubicin, Mitochondria, Protein acetylation

Citation formats


Ferreira, L. L., Cervantes, M., Froufe, H. J. C., Egas, C., Cunha-Oliveira, T., Sassone-Corsi, P., & Oliveira, P. J. (2020). Doxorubicin persistently rewires cardiac circadian homeostasis in mice. Archives of Toxicology, 94(1), 257-271.


Ferreira, LL, Cervantes, M, Froufe, HJC, Egas, C, Cunha-Oliveira, T, Sassone-Corsi, P & Oliveira, PJ 2020, 'Doxorubicin persistently rewires cardiac circadian homeostasis in mice', Archives of Toxicology, vol. 94, no. 1, pp. 257-271.