ANTHRAWES · Interference of anthracyclines with cardiac energy signalling: implications for drugs, cardiotoxicity and oncogenic growth
6РП — Действия „Мария Кюри“
- Период
- 2007-04-01 → 2009-03-31
- Финансиране от ЕС
- 213 456 €
- Участници
- 1
- Схема
- EIF
Линиите свързват координатора с партньорите.
Накратко на български
Антрациклините, като лекарството доксорубицин, влияят върху енергийния обмен и реакцията на сърдечните клетки към стреса. Разбирането на тези механизми помага да се намали токсичното действие на противораковите препарати върху сърцето.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - ANTHRAWES (Interference of anthracyclines with cardiac energy signalling: implications for drugs, cardiotoxicity and oncogenic growth)
Drugs of the anthracycline group, in particular doxorubicin (Adriamycin), are among the most effective and extensively used anti-cancer agents. However, their use is limited by a significant risk of cardiotoxicity, whose molecular mechanisms are still not entirely clear. The aim of the project was to improve our understanding of these mechanisms, in particular in regard to impaired cellular energy metabolism, which is especially harmful to myocardium, requiring continuous energy supply to sustain contractile performance. A genome-wide analysis of antracycline-induced changes in gene expression and the proteome/phospho-proteome was combined with a targeted analysis of the AMPK signalling cascade, emerging as the central signalling pathway in regulating energy metabolism. Using a perfused heart model and cultured cardiomyocytes, we have obtained further evidence that doxorubicin decreases basal phosphorylation of AMPK and related up- and downstream kinases, while the AKT pathway is activated. Doxorubinin-induced changes in the transcriptome revealed further putative toxicity mechanisms, in particular rapid down-regulation of many single genes and entire pathways involved in the cellular response to stress like heat shock or oxidative, hypoxic, and genotoxic stress. Our results propose that a blunted response to stress or reduced "danger signalling" leads among others to impaired cellular energetics and is a prime component of toxic doxorubicin action and can drive cardiac cells into pathology. Protective effects of creatine and phosphocreatine were demonstrated.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Anthracyclines belong to the most efficient drugs of cancer chemotherapy. However, their use is limited by severe cardiotoxicity, whose molecular triggers are not fully understood. Our aim is to analyse novel aspects of cardiac response to anthracyclines, namely signalling pathways regulating cardiac energetics. The ability to respond to altered energy supply or demand is particularly important for heart to maintain its contractile performance. Our approach will integrate a non-biased global analysis of antracycline-induced changes in gene expression and proteome/phospho-proteome with a targeted analysis of the signaling pathway of AMP-activated protein kinase (AMPK).AMPK is a key sensor and regulator of cellular energy state and the drug reduces basic AMPK phosphorylation as we showed recently. The multidisciplinary approach combining biophysical, biochemical, molecular and physiological state-of-the-art techniques will (i) apply different model systems as recombinant protein, cultured cardiomyocytes, isolated perfused rat heart, and cancer cells for comparison, (ii) explore regulatory cross-talk between the AMPK cascade and other signalling pathways or key regulators of cardiac energy metabolism (e.g. creatine kinase), (iii) screen a library of cardioprotective compounds.In scientific terms, we will identify anthracycline-induced changes in the cardiac energetic network and other signalling pathways susceptible to mediate drug cardiotoxic, and possibly anticancer effects. This can provide potent means to modulate drugs toxic and therapeutic activity. In terms of training, fellows goal is to acquire expertise in different cardiac models and in integrative approach (from molecular to physiological) to cardiac bioenergetics and non-scientific skills in a leading medically oriented research environment to amend her multidisciplinary portfolio with the long-term goal to obtain a permanent, leading position in research, e.g. as professor or clinical researcher.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITE JOSEPH FOURIER - GRENOBLE 1 · GRENOBLEКоординаторФранция
Връзки
Данни: CORDIS, © Европейски съюз