Abstract
Doxorubicin (DOX) is a widely used chemotherapeutic drug, but its utility is compromised by cardiotoxicity, which can be debilitating and potentially lethal. Current diagnostic methods assessing structural and contractile dysfunction are often unable to detect its onset before irreversible damage has occurred. The relative importance of the various mechanisms underlying DOX-induced cardiotoxicity remain unclear, but iron overload and oxidative stress are known to play an important role. Cancer patients with pre-existing cardiac iron overload due to blood transfusion or genetic disorders are known to be at elevated risk.The aim of this thesis was to examine the relationship between cardiac iron overload and metabolic dysfunction in a clinically relevant in vivo preclinical model of chronic DOX- induced cardiotoxicity.
An ICP-MS based protocol was optimised for the measurement of total and mitochondrial cardiac iron; cardiac function was monitored by echocardiography and metabolic profiling was performed by high field NMR. Two clinically relevant rat models were developed and characterised, 1) cardiac iron overload using iron dextran to emulate the elevated levels of iron observed in cancer patients undergoing DOX treatment, and 2) a clinically relevant model of chronic DOX-induced cardiotoxicity. These models were used to test whether pre-existing iron overload exacerbates chronic DOX-induced cardiotoxicity, and to investigate the potential cardioprotective efficacy of pre-treatment with the iron chelator deferiprone.
A dose-dependent reduction in LVEF and alterations in cardiac metabolism six weeks after the end of DOX treatment was observed. Total cellular cardiac iron did not show significant elevation with the administration of clinically equivalent DOX doses (2 mg/kg/wk and 3 mg/kg/wk for four weeks). These results suggest that total cardiac iron is not perturbed long term in chronic DOX-induced cardiotoxicity, however the importance of labile iron versus bound may be more significant.
It was found that iron loading did not exacerbate cardiac dysfunction or alter cardiac metabolism within the timeframe of our study and at the dosage used. However, iron loading did induce a non-significant reduction in LVEF compared to DOX treatment alone. This difference may become more pronounced over time due to the progressive nature of chronic DOX-induced cardiotoxicity, potentially impacting life expectancy beyond the 6-week observation period. Deferiprone did mitigate the decline in LVEF by normalizing it to levels observed in animals treated with DOX alone. Though LVEF remained significantly reduced compared to control and baseline levels, pre-treatment of deferiprone may hold clinical significance in the longer term as chronic DOX-induced cardiotoxicity progresses.
Lastly, preliminary investigations on DOX lipotoxicity revealed that DOX treatment invoked systemic changes in lipid metabolism (measured by elevated serum lipid levels and altered liver metabolism), suggesting additional mechanisms may potentiate anthracycline-induced cardiotoxicity. This suggests the possibility of testing the cardioprotective potential of statins on the development of DOX-induced cardiotoxicity using our in vivo models.
| Date of Award | 1 Oct 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Richard Southworth (Supervisor) & Thomas Eykyn (Supervisor) |