Evaluation of iron chelators for cancer therapy, alone or in combination with DNA repair inhibitors

Carter, Andrew W. (2024) Evaluation of iron chelators for cancer therapy, alone or in combination with DNA repair inhibitors. Doctoral thesis, Northumbria University.

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Abstract

This thesis focussed on iron as a critical target for cancer therapy. The thesis focuses on a number of approaches to this: measurement of iron, the development and in vitro assessment of a novel probe (AC01) that seeks to identify tumours that will be sensitive to iron chelation using SK4, a novel chelator that enters through LAT1 and the combination of iron chelators with DNA repair inhibitors. A method to measure iron in cell-free conditions was developed and optimised; however, a key finding was that the measurement of iron in cells in a simple and reliable manner remains an area that needs more study.

The development of AC01 as a diagnostic probe holds promise; however, whilst there was some evidence that the LAT1 transporter was utilised, only a modest reduction in fluorescence at high concentrations of LAT1 inhibitor suggests that AC01 has another mode of entry, likely due to its lipophilicity.

The key findings of the thesis are that iron chelators are synergistic with DNA repair inhibitors in the cancer cell line of MDA MB 231 breast cancer and that this synergy is present even when inhibiting the cell growth of 95% of MDA MB 231 cells. The ATM DNA repair inhibitor AZD0156, in combination with di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), was the most synergistic combination in MDA MB 231 cells with a CI of 0.059 inhibiting 95% of MDA MB 231 cell proliferation. This combination was more than 100-fold more selective for MDA MB 231 cells than the normal human dermal cell line (HDF). Taken together, these findings demonstrate that iron is a valid target for the development of novel therapies in cancer and that the combination with DNA repair inhibitors holds particular promise.

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