Descoberto novo mecanismo subjacente à cardiotoxicidade da Doxorrubicina

Um grupo de investigadores do Centro de Neurociências e Biologia Celular (CNC) da Universidade de Coimbra (UC), descobriu um novo mecanismo envolvido na cardiotoxicidade do fármaco anticancerígeno Doxorrubicina (ou Adriamicina) que poderá vir a ser explorado como novo alvo terapêutico para contrariar os efeitos secundários da quimioterapia. A Doxorrubicina é um agente quimioterapêutico poderoso mas que a longo-prazo desencadeia graves efeitos secundários que comprometem a função cardíaca dos pacientes. As células cardíacas necessitam de quantidades elevadas de energia, e a cardiotoxicidade da Doxorrubicina tem sido associada a uma perda da função da mitocôndria, o organelo celular também conhecido como “central elétrica da célula”. O estudo publicado na revista científica internacional “Toxicology and Applied Pharmacology” utilizou um modelo de células cardíacas derivadas de células estaminais que preserva a capacidade de contração, a qual é sustentada por um grande fornecimento de energia. Os autores mostraram que a disfunção mitocondrial associada à cardiotoxicidade da Doxorrubicina envolve a ativação da sinalização mediada pela proteína p53 e uma perda de atividade da enzima desidrogenase do piruvato (PDH). Usando um ativador desta enzima foi possível melhorar a função mitocondrial e os níveis de energia nas células tratadas com Doxorrubicina, incentivando estudos posteriores sobre potenciais vantagens da quimioterapia combinada com ativadores da PDH. O financiamento do trabalho foi obtido através da Fundação para a Ciência e a Tecnologia, do COMPETE- Programa Operacional Fatores de Competitividade, QREN, da União Europeia (FEDER- Fundo Europeu de Desenvolvimento Regional).

Autores e Afiliações:
Teresa Cunha-Oliveira, Luciana L. Ferreira, Ana Raquel Coelho, Cláudia M. Deus, Paulo J. Oliveira

CNC, Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park, 3060-197 Cantanhede, Portugal -Institute for Interdisciplinary Research (I.I.I.), University of Coimbra, 3030-789 Coimbra, Portugal

Abstract:
Title Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes. 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.

Revista: Toxicology and Applied Pharmacology 348:1-13

Link: https://www.sciencedirect.com/science/article/pii/S0041008X18301443