Crosstalk Between Iron Homeostasis And Nitric Oxide Signalling: Impact On Cancer Cell Viability
The element iron (Fe) is essential for mammals since many enzymes require Fe as a cofactor for metabolic processes. Fe regulation is extremely important to maintain Fe homeostasis as Fe overload and Fe deprivation are cytotoxic. Fe overload can cause oxidative damage via excessive production of reactive oxygen species (ROS). On the other hand, Fe deprivation can inhibit cellular growth and lead to apoptosis. Iron regulatory proteins (IRPs) are important for maintaining cellular Fe homeostasis. Regulation of these proteins involves the redox status of the iron-sulphur (Fe-S) clusters of the enzyme aconitase. IRPs are very sensitive to oxidative stress. Excessive exposure of these regulatory proteins to ROS will disrupt cellular Fe regulation by inducing Fe trafficking in cells. The major cellular systems (e.g. mitochondrial respiratory chain) are dependent on Fe for their functionality. With a lack of Fe, these systems will be affected. The susceptibility of cells to oxidative damage will increase under Fe deprivation conditions. Therefore, potentially both Fe overload and Fe deprivation are beneficial for cancer therapy if they could be selectively induced within a tumour. In the present study, nitric oxide (•NO) released by a novel photoactive agent, tDSNO, was studied as a means of selectively impairing Fe homeostasis and exacerbating the effect of Fe deprivation. The exposure to •NO was hypothesised to cause toxicity to cancer cells by exaggerating the stress conditions, which is the characteristic of both Fe overload and Fe deprivation pathways. Results showed that the exposure of breast cancer cells (MDA-MB-231) and lung cancer cells (A549) to •NO under normal Fe homeostasis conditions was unable to promote Fe overload as the intracellular Fe content did not significantly increase relative to control (p>0.05). However, the efficacy of tDSNO was potentiated under conditions of Fe deprivation. A maximum cellular death of 59.1 ± 1.2% was observed after 24 h of exposure to 40 µM of tDSNO at 37oC (p<0.05), while under these conditions, the drug tDSNO displayed a low toxicity in cells with normal Fe homeostasis. Therefore, the toxic effect of tDSNO in cancer cells was substantially enhanced under Fe deprivation conditions. It was then concluded that this novel drug could be more effective if used in combination with Fe chelation therapy.
Advisor: Giles, Gregory
Degree Name: Master of Science
Degree Discipline: Pharmacology and Toxicology
Publisher: University of Otago
Keywords: Nitric oxide; Iron homeostasis; Nitric oxide donors; Iron chelators; Breast cancer; Lung cancer
Research Type: Thesis