Hypoxia tolerant copper(II)-based therapeutics: An alternative treatment for chemo-resistant breast cancer?

Tumours that are greater than 2-3 mm in diameter are characterised by having hypoxic (low oxygen) regions and their resistance to DNA-targeting drugs has been attributed to changes in biochemical pathways within hypoxic cells, which results in inactivation of the drug, the pathway targeted or the upregulation of alternative biochemical pathways. Some current chemotherapeutics used to treat breast cancer cause DNA interaction/disruption or disruption of cellular pathways with subsequent or concomitant generation of reactive oxygen species (ROS). However, enhancing ROS production under conditions of hypoxia may initiate a redox adaptation response which promotes cancer cell viability. The aim of this project is to establish whether copper(II) complexes, which maintain or enhance their cytotoxicity in hypoxic conditions, can be developed as potential therapeutic targets for treatment of breast cancer. We have identified two series of cytotoxic copper complexes which have opposing abilities to generate reactive oxygen species in the MCF-7 breast cancer-derived cell line. The contrast in behaviour of the copper complexes is also evident in their solution behaviour and their physicochemical properties. Therefore, physicochemical solution studies will be coupled with cytotoxicity studies under normoxic and hypoxic conditions to identify if these compounds have therapeutic value under hypoxic conditions.