Doctoral Degrees (Physiological Sciences)

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Browsing Doctoral Degrees (Physiological Sciences) by Author "Govender, Yogeshni (Jenelle)"

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    Mitochondrial catastrophe during doxorubicin-induced cardiotoxicity : An evaluation of the protective role of melatonin.
    (Stellenbosch University, 2017-03) Govender, Yogeshni (Jenelle); Engelbrecht, Anna-Mart; Loos, Ben; Marais, Erna; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Introduction: Anthracyclines, such as doxorubicin (DXR), are among the most valuable treatments for various cancers, but their clinical use is limited due to detrimental side-effects such as cardiotoxicity. The abundance of mitochondria in cardiomyocytes closely links mitochondrial function with myocardial function. Mitochondrial dysfunction has emerged as a critical element in the development of DXR-induced cardiotoxicity. In light of this scenario, melatonin (MLT) is a potent anti-oxidant, is non-toxic, is dually oncostatic and cardio-protective, and has been shown to influence mitochondrial homeostasis and function. Both endogenously produced and exogenously administered MLT during or prior chemotherapy shows great promise in this therapeutic avenue as demonstrated in several studies. Although research support the mitochondrial protective role of MLT, the exact mechanisms by which MLT confers mitochondrial protection in the context of DXR-induced cardiotoxicity remains to be elucidated. Aims: The aim of this study was to investigate the effect of MLT on the following mitochondrial and cellular parameters: mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential, mitochondrial fission and fusion, mitochondrial bioenergetics and biogenesis, sirtuin activity, autophagy and cell death in an in vitro model of DXR-induced cardiotoxicity. Furthermore, the effect of MLT on cardiac function and tumor growth was assessed in a tumor-bearing rat model of acute DXR-induced cardiotoxicity. Materials and Methods: H9c2 rat cardiomyoblasts were pre-treated with MLT (10 μM) for 24 hours followed by DXR treatment (3 μM) for 24 hours. Following treatment, the above mentioned mitochondrial and cellular parameters were assessed using immunoblot analysis, mitochondrial respiration analysis, flow cytometry, fluorescence microscopy and luciferase-based assays. Sprague Dawley female rats (16-18 weeks old), were inoculated with LA7 rat tumor cells. Animals received DXR (3 intraperitoneal injections of 4 mg/kg at 3-day intervals, 12 mg/kg cumulative dose) and/or received MLT (6 mg/kg) daily in their drinking water. Tumors were measured daily using digital calipers and tumor volumes calculated. Animal weights were recorded daily. Rat hearts were used to conduct isolated heart perfusions to assess cardiac function and thereafter, heart tissue was used for immunoblot analysis. Results: DXR treatment significantly increased cell death, mitochondrial ROS levels and mitochondrial fission and these effects were significantly reduced with MLT pre-treatment. Furthermore, MLT pre-treatment significantly increased mitochondrial membrane potential, mitochondrial biogenesis and cellular ATP levels reduced by DXR treatment. Cardiac output and total work performance of the heart was significantly increased in rats treated with DXR+MLT in comparison to rats treated with DXR alone. In addition, body and heart weights were significantly reduced in DXR-treated rats in comparison to DXR+MLT treated rats. Tumor volumes were significantly reduced in DXR+MLT-treated rats on Day 8 in comparison to DXR-treated rats. Discussion and Conclusion: The results obtained from the current study indicates that MLT treatment confers a cardio-protective effect by maintaining mitochondrial function, increasing cardiomyocyte survival and improving cardiac function during DXR-induced cardiotoxicity. Furthermore, MLT treatment alone suppresses the growth of tumors. The combination of DXR+MLT treatment rapidly reduced tumor growth, suggesting that MLT enhances the oncostatic activity of DXR. The unique ability of MLT to be both cardio-protective and oncostatic during DXR-induced cardiotoxicity is promising for the field of cardio-oncolocgy.