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Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes.
Toxicol Appl Pharmacol. 2018 06 01; 348:1-13.TA

Abstract

Doxorubicin (DOX) is a widely used anticancer drug that could be even more effective if its clinical dosage was not limited because of delayed cardiotoxicity. Beating stem cell-derived cardiomyocytes are a preferred in vitro model to further uncover the mechanisms of DOX-induced cardiotoxicity. Our objective was to use cultured induced-pluripotent stem cell(iPSC)-derived mouse cardiomyocytes (Cor.At) to investigate the effects of DOX on cell and mitochondrial metabolism, as well as on stress responses. Non-proliferating and beating Cor.At cells were treated with 0.5 or 1 μM DOX for 24 h, and morphological, functional and biochemical changes associated with mitochondrial bioenergetics, DNA-damage response and apoptosis were measured. Both DOX concentrations decreased ATP levels and SOD2 protein levels and induced p53-dependent caspase activation. However, differential effects were observed for the two DOX concentrations. The highest concentration induced a high degree of apoptosis, with increased nuclear apoptotic morphology, PARP-1 cleavage and decrease of some OXPHOS protein subunits. At the lowest concentration, DOX increased the expression of p53 target transcripts associated with mitochondria-dependent apoptosis and decreased transcripts related with DNA-damage response and glycolysis. Interestingly, cells treated with 0.5 μM DOX presented an increase in PDK4 transcript levels, accompanied by an increase in phospho-PDH and decreased PDH activity. This was accompanied by an apparent decrease in basal and maximal oxygen consumption rates (OCR) and in basal extracellular acidification rate (ECAR). Cells pre-treated with the PDK inhibitor dichloroacetate (DCA), with the aim of restoring PDH activity, partially recovered OCR and ECAR. The results suggest that the higher DOX concentration mainly induces p53-dependent apoptosis, whereas for the lower DOX concentration the cardiotoxic effects involve bioenergetic failure, unveiling PDH as a possible therapeutic target to decrease DOX cardiotoxicity.

Authors+Show Affiliations

CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park, Cantanhede, Portugal. Electronic address: teresa.oliveira@uc-biotech.pt.CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park, Cantanhede, Portugal.CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park, Cantanhede, Portugal; Institute for Interdisciplinary Research (I.I.I.), University of Coimbra, 3030-789 Coimbra, Portugal.CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park, Cantanhede, Portugal; Institute for Interdisciplinary Research (I.I.I.), University of Coimbra, 3030-789 Coimbra, Portugal.CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park, Cantanhede, Portugal; Institute for Interdisciplinary Research (I.I.I.), University of Coimbra, 3030-789 Coimbra, Portugal.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29653124

Citation

Cunha-Oliveira, Teresa, et al. "Doxorubicin Triggers Bioenergetic Failure and P53 Activation in Mouse Stem Cell-derived Cardiomyocytes." Toxicology and Applied Pharmacology, vol. 348, 2018, pp. 1-13.
Cunha-Oliveira T, Ferreira LL, Coelho AR, et al. Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2018;348:1-13.
Cunha-Oliveira, T., Ferreira, L. L., Coelho, A. R., Deus, C. M., & Oliveira, P. J. (2018). Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes. Toxicology and Applied Pharmacology, 348, 1-13. https://doi.org/10.1016/j.taap.2018.04.009
Cunha-Oliveira T, et al. Doxorubicin Triggers Bioenergetic Failure and P53 Activation in Mouse Stem Cell-derived Cardiomyocytes. Toxicol Appl Pharmacol. 2018 06 1;348:1-13. PubMed PMID: 29653124.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes. AU - Cunha-Oliveira,Teresa, AU - Ferreira,Luciana L, AU - Coelho,Ana Raquel, AU - Deus,Cláudia M, AU - Oliveira,Paulo J, Y1 - 2018/04/11/ PY - 2018/01/11/received PY - 2018/04/06/revised PY - 2018/04/08/accepted PY - 2018/4/14/pubmed PY - 2018/11/27/medline PY - 2018/4/14/entrez KW - Apoptosis KW - Cancer chemotherapy KW - Cardiotoxicity KW - Doxorubicin KW - Mitochondria KW - Pyruvate Dehydrogenase (PDH) SP - 1 EP - 13 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 348 N2 - Doxorubicin (DOX) is a widely used anticancer drug that could be even more effective if its clinical dosage was not limited because of delayed cardiotoxicity. Beating stem cell-derived cardiomyocytes are a preferred in vitro model to further uncover the mechanisms of DOX-induced cardiotoxicity. Our objective was to use cultured induced-pluripotent stem cell(iPSC)-derived mouse cardiomyocytes (Cor.At) to investigate the effects of DOX on cell and mitochondrial metabolism, as well as on stress responses. Non-proliferating and beating Cor.At cells were treated with 0.5 or 1 μM DOX for 24 h, and morphological, functional and biochemical changes associated with mitochondrial bioenergetics, DNA-damage response and apoptosis were measured. Both DOX concentrations decreased ATP levels and SOD2 protein levels and induced p53-dependent caspase activation. However, differential effects were observed for the two DOX concentrations. The highest concentration induced a high degree of apoptosis, with increased nuclear apoptotic morphology, PARP-1 cleavage and decrease of some OXPHOS protein subunits. At the lowest concentration, DOX increased the expression of p53 target transcripts associated with mitochondria-dependent apoptosis and decreased transcripts related with DNA-damage response and glycolysis. Interestingly, cells treated with 0.5 μM DOX presented an increase in PDK4 transcript levels, accompanied by an increase in phospho-PDH and decreased PDH activity. This was accompanied by an apparent decrease in basal and maximal oxygen consumption rates (OCR) and in basal extracellular acidification rate (ECAR). Cells pre-treated with the PDK inhibitor dichloroacetate (DCA), with the aim of restoring PDH activity, partially recovered OCR and ECAR. The results suggest that the higher DOX concentration mainly induces p53-dependent apoptosis, whereas for the lower DOX concentration the cardiotoxic effects involve bioenergetic failure, unveiling PDH as a possible therapeutic target to decrease DOX cardiotoxicity. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/29653124/Doxorubicin_triggers_bioenergetic_failure_and_p53_activation_in_mouse_stem_cell_derived_cardiomyocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(18)30144-3 DB - PRIME DP - Unbound Medicine ER -