AbstractThe antioxidant Tiron has been shown to protect against reactive oxygen species (ROS) related injury in several experimental models. However, to date, there is little information on the effects of Tiron in the heart. Therefore, the focus of this thesis was to identify and examine the effects of Tiron on the myocardium in a non-clinical setting using 3-month-old, male Sprague-Dawley rats. In addition, the effect of Tiron against Doxorubicin, a potent anti-cancer drug, was also investigated in naïve and ischaemia/reperfusion (I/R) conditions in the myocardium. The anticancer properties of Doxorubicin in the co-treatment with Tiron were assessed in human leukaemia HL60 and human liver carcinoma HepG2 cancer cell lines.
The results of these studies showed that under normoxic conditions, treatment with low concentrations of Tiron (0.25-1mM) did not reveal a negative effect on cardiac viability. However, administration of Tiron at high concentrations significantly increased the infarct size and decreased cell viability, indicating a pro-oxidant effect in the myocardium in normoxic settings. In the context of simulated regional ischaemia and reperfusion in the isolated hearts, treatment with Tiron (0.25-2.5mM) showed a significant reduction in the infarct size. In addition, an improved cellular viability, an increased concentration of the pro-survival Akt and a decrease in caspase-3 activity was also reported in Tiron treated groups when compared to ischaemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) control group.
Concomitant treatment of Tiron with Doxorubicin in both normoxic and ischaemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) conditions attenuated myocardial injury, improved the cardiac function and cellular viability, reduced cellular oxidative stress and caspase-3 levels when compared to Doxorubicin treated groups. Interestingly, in human cancerous HL60 and HepG2 cell 3 lines, 24-hour treatment with Tiron (0.25-2.5mM) alone did not cause significant changes in the cell viability, caspase-3 and reactive oxygen species (ROS) levels. Co-administration of Tiron with Doxorubicin did not impact the cytotoxic effects of Doxorubicin, which were marked by a decrease in cell viability and an increase in caspase-3 activity. In conclusion, the results presented in this thesis showed for the first time that Tiron exhibited cardioprotective properties in both myocardial ischaemia/reperfusion (MI/R) injury and against Doxorubicin induced-cardiotoxicity via its antioxidative properties. Besides the beneficial cardioprotective effects, Tiron did not alter the efficacy of Doxorubicin in human cancerous cell lines, highlighting the potential use of Tiron as an adjunctive therapy that selectively reduces the toxic side effects of Doxorubicin in the heart without altering its anticancer potency.
|Date of Award||4 Jul 2019|
|Supervisor||Christopher Mee (Supervisor), Mayel Gharanei (Supervisor), Ellen Hatch (Supervisor) & Helen Maddock (Supervisor)|