ROCKLEY, KIMBERLY,LOUISE (2018) In Vitro Evaluation of Anthracycline-induced Cardiotoxicity and Mitigation by Perturbation of Angiotensin Signalling. Doctoral thesis, Durham University.
|PDF - Accepted Version|
Cardiotoxicity is a major complication of many anticancer therapies, particularly anthracyclines, which impacts the quality of life and overall survival of patients. Manifesting as both an acute toxicity and more frequently a chronic toxicity occurring months or years after conclusion of therapy, there is an urgent need for greater understanding of the molecular mechanisms responsible for these toxicities and identification of therapeutic strategies to mitigate and overcome this issue. Improved in vitro models for accurate prediction and modelling of these cardiac liabilities is therefore of crucial importance.
Recently, clinical studies have demonstrated that drugs which perturb angiotensin signalling may reduce the cardiotoxicity of anthracyclines. However, despite showing promise, the mechanism of toxicity is unresolved and the molecular relationship to angiotensin signalling in the heart is currently unknown. Furthermore, the majority of in vitro cardiotoxicity studies to date have either used inappropriate cell models or utilised end-point assays, both strategies that fail to account for the physiological parameters of cardiac cells and the progressive nature of human toxicity development.
This study has qualified the use of hiPSC-derived cardiomyocytes and the human AC10 cardiomyocyte cell line paired with impedance-based systems (xCELLigence technology) for detection of both structural and functional cardiotoxicity. A range of pharmacological and biological mediators were used to qualify these technologies, with both structural hypertrophy and physiological contractility monitorable. A major advantage of these systems over others is that longer-term real-time non-invasive experiments can be conducted, thus allowing recapitulation of the progressive nature of human toxicity development and subsequently a robust clinically relevant method for assessing drug-induced cardiotoxicity.
Using these models and technologies, this study demonstrates induction of cardiomyocyte hypertrophy by anthracyclines which is reduced by blockade of angiotensin signalling, thus implying a relationship at the cardiomyocyte level between anthracycline-induced cardiotoxicity and angiotensin signalling. Furthermore, anthracycline-induced elevated expression of the angiotensin type I receptor and several genes implicated in angiotensin II signalling in this study provides further evidence for a direct molecular relationship between anthracycline-induced cardiotoxicity and angiotensin signalling, with clear translational potential for clinical mitigation of this dose-limiting toxicity in the treatment of cancer.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Keywords:||Cardio-oncology, cardiotoxicity, anthracyclines, angiotensin signalling, hypertrophy, xCELLigence, doxorubicin, angiotensin receptor blockers, toxicity mitigation.|
|Faculty and Department:||Faculty of Social Sciences and Health > Medicine and Health, School of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||16 May 2018 12:36|