The Effect of Photoactivation on the Mechanism of Action of tDodSNO
|dc.identifier.citation||Nield-Patterson, A. (2015). The Effect of Photoactivation on the Mechanism of Action of tDodSNO (Thesis, Master of Science). University of Otago. Retrieved from http://hdl.handle.net/10523/5842||en|
|dc.description.abstract||Since the discovery and identification of nitric oxide (NO) in vivo more than 30 years ago, a wealth of knowledge has been collected regarding its biological action. More recently, NO has been shown to be a valuable chemotherapeutic, however its application clinically has been hindered by its short half-life and toxic systemic effects. The development of NO donors has provided an avenue by which NO may be administered without unwanted side-effects, with the S-nitrosothiol class of donors showing particular promise in this regard. The recent development of a novel photoactivated NO donor, tert-Dodecane S-nitrosothiol (tDodSNO), has further improved upon selectively controlling NO generation. With the application of light, the decomposition of tDodSNO may be controlled, making the drug relatively inert in its absence, providing a mechanism by which NO release may be modulated. tDodSNO has shown some promise as a cytotoxic agent in previous studies; however, its combination with other well established chemotherapeutics may show more potential. Despite this, little is still known about the immediate cellular action of tDodSNO following catalysis of the pro-drug to liberate NO. The present study aimed to investigate the mechanism of action of the novel photoactivated NO donor drug tDodSNO in order to establish therapeutic uses in combination with other well established chemotherapeutics. To assess this, a model of cancer was established in the MDA-MB-231 cell line and the outcomes of tDodSNO treatment were determined. At concentrations greater than 50 μM, tDodSNO was shown to increase cellular oxidation in a photoactivation dependent manner by up to 20.6± 0.9%. This increase in oxidation initiated cellular lipid peroxidation in a concentration-dependent manner; however this effect was not modulated by light exposure, indicating it occurred by an independent mechanism to cellular oxidation. Further, nitration and S-nitrosylation of proteins was observed at the highest 100 μM concentration, while thiol oxidation was not altered. The tumour suppressor protein, p53 was found to be accumulated 24 hours post-treatment with a 1.37 ± 0.9 fold-increase from control with 100 µM photoactivated tDodSNO, indicating cellular stress and potential DNA damage. Some of the cellular changes observed were further enhanced by irradiation of tDodSNO, which induced rapid decomposition to release NO. These findings implicate a wide range of cellular effects of tDodSNO and provided evidence for the use of tDodSNO in combination with a number of other chemotherapeutics to produce synergistic effects.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.subject||Nitric Oxide Donor|
|dc.subject||Reactive Oxygen Species|
|dc.title||The Effect of Photoactivation on the Mechanism of Action of tDodSNO|
|thesis.degree.discipline||Department of Pharmacology and Toxicology|
|thesis.degree.name||Master of Science|
|thesis.degree.grantor||University of Otago|
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