Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/84848
Title: | Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes | Authors: | Cunha-Oliveira, Teresa Ferreira, Luciana L Coelho, Ana Raquel Deus, Cláudia M Oliveira, Paulo J |
Issue Date: | 2018 | Serial title, monograph or event: | Toxicology and Applied Pharmacology | Volume: | 348 | 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. | URI: | https://hdl.handle.net/10316/84848 | ISSN: | 1096-0333 | DOI: | 10.1016/j.taap.2018.04.009 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
32_Cunha-Oliveira 2018.pdf | 2.7 MB | Adobe PDF | View/Open |
SCOPUSTM
Citations
39
checked on Sep 23, 2024
WEB OF SCIENCETM
Citations
5
34
checked on Sep 2, 2024
Page view(s)
333
checked on Sep 24, 2024
Download(s) 50
1,028
checked on Sep 24, 2024
Google ScholarTM
Check
Altmetric
Altmetric
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.