The Oxidative Modifications to Cancer Cells Induced by Three Redox-Active Drugs: Auranofin, PEITC and TDSNO
Redox homeostasis is of critical importance for normal cellular functions. The intracellular environment is maintained in a reduced state, upon which, reactive oxygen (ROS) and nitrogen (RNS) species oxidise cellular components and induce functional changes. Proteins are important targets of redox signalling, as their diverse cellular functions may be regulated by the oxidation of specific amino acid residues. The thiol groups of cysteine residues are particularly important due to their roles in activity, intra- and inter-molecular bonding. Abnormalities in the cellular redox state underlie many forms of cancer; these exhibit a shift in the redox balance towards a more oxidative state. Therefore, the pharmacological induction of oxidative modifications to the proteome will selectively induce death in cancer cells. This study aimed to assess the chemical changes induced by three redox-active drugs, auranofin, PEITC and a novel light-sensitive S-nitrosothiol, known as TDSNO, because of their potential thiol modifying activity. A therapeutic range was established for each drug and FTIR spectroscopy was used to identify the chemical effects induced by non-toxic and cytotoxic concentrations. All three compounds induced significant changes to the proteome, however TDSNO and PEITC induced additional minor changes to other cellular components. Non-toxic concentrations of both auranofin and PEITC induced larger chemical changes than cytotoxic concentrations, while a linear correlation to the photo-activated TDSNO concentration was observed. Despite the differences, the changes induced by the three drugs were predominantly co-localised with the nucleus and potentially the endoplasmic reticulum. Furthermore, it was found that the modulation of the glycolytic pathway altered the cytotoxicity of TDSNO. There is therefore potential for these drugs to be used in combination and in the presence of inhibitors of glycolysis, for the selective treatment of cancer.
Advisor: Giles, Greg
Degree Name: Master of Science
Degree Discipline: Pharmacology & Toxicology
Publisher: University of Otago
Keywords: FTIR; Infrared; Spectroscopy; Synchrotron; Auranofin; PEITC; Phenethyl Isothiocyanate; TDSNO; Redox; Pharmacology; Cancer
Research Type: Thesis