Metabolic Manipulation of Glutathione as an Anticancer Therapeutic Target
| dc.contributor.advisor | Perry, Christopher G. R. | |
| dc.contributor.author | Turnbull, Patrick Carson | |
| dc.date.accessioned | 2020-05-11T12:47:44Z | |
| dc.date.available | 2020-05-11T12:47:44Z | |
| dc.date.copyright | 2019-08 | |
| dc.date.issued | 2020-05-11 | |
| dc.date.updated | 2020-05-11T12:47:44Z | |
| dc.degree.discipline | Kinesiology & Health Science | |
| dc.degree.level | Doctoral | |
| dc.degree.name | PhD - Doctor of Philosophy | |
| dc.description.abstract | Many cancers rely on glycolysis rather than mitochondrial metabolism as their primary source of ATP. As such, altering this balance through forced mitochondrial activation has yielded promising results as anticancer therapies for specific cancers. In previous studies, stimulated mitochondrial activation through exposure to palmitoylcarnitine, a mitochondrial fatty-acid substrate, resulted in colon and prostate cancer-specific cell death, however, mitochondrial fatty-acid oxidation led to increased cervical cancer growth. The primary mechanism for promoting antineoplastic effects in response to palmitoylcarnitine is through oxidative stress, namely through production of superoxide and subsequently hydrogen peroxide (H2O2). However, H2O2 can be hormetic in nature, whereby elevated H2O2 can result in deleterious effects, yet modest H2O2 can promote growth. Therefore, the ability of the cell to regulate H2O2 is of apparent importance, highlighting glutathione, the most abundant intracellular antioxidant, as a potential determinant of cancer survival following palmitoylcarnitine. The purpose of this dissertation was to first determine the response of glutathione to palmitoylcarnitine within relation to cell survival. Following palmitoylcarnitine, glutathione responses seemingly dictated cell fate, whereby HT29 colorectal carcinoma cells displayed decreased cell survival, increased H2O2 and decreased glutathione. CCD 841 normal colon cells were insensitive to palmitoylcarnitine despite increased H2O2, yet maintained glutathione. HepG2 hepatocarcinoma cells, cells associated with fatty-acid stimulated disease progression, increased cell growth with coordinated increases in glutathione following palmitoylcarnitine. This dissertation considered recent evidence that suggests combined inhibition of glutathione and thioredoxin, another intracellular antioxidant, is required for anticancer effects in established tumours. Auranofin is a putative inhibitor of the thioredoxin system. HCT 116 p53-/- cells were resistant to auranofin at doses that HCT 116 p53+/+ cells were sensitive to, however concurrent exposure of auranofin and glutathione depletion through serine and glycine starvation sensitized HCT 116 p53-/- cells to decreased cell survival. This observation was repeated in a p53mutant cell line, HT29. Taken together, this thesis identifies glutathione as an important regulator in determining cell fate in response to palmitoylcarnitine, the dual role of glutathione and thioredoxin in influencing cell fate in relation to p53, and highlights the potential of redox-buffering systems as therapeutic targets for selective antineoplastic growth. | |
| dc.identifier.uri | https://hdl.handle.net/10315/37420 | |
| dc.language | en | |
| dc.rights | Author owns copyright, except where explicitly noted. Please contact the author directly with licensing requests. | |
| dc.subject | Biochemistry | |
| dc.subject.keywords | Cancer | |
| dc.subject.keywords | Bioenergetics | |
| dc.subject.keywords | Mitochondria | |
| dc.subject.keywords | Glutathione | |
| dc.subject.keywords | Reactive oxygen species (ROS) | |
| dc.subject.keywords | Thioredoxin | |
| dc.subject.keywords | Metabolism | |
| dc.title | Metabolic Manipulation of Glutathione as an Anticancer Therapeutic Target | |
| dc.type | Electronic Thesis or Dissertation |
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