The Development of Anti-Breast Cancer Stem Cell Copper(II) Complexes

A subpopulation of cancer cells, called cancer stem cells (CSCs), are thought to be responsible for cancer relapse and metastasis, phenomena which are the cause of the majority of cancer deaths. CSCs are highly treatment resistant and are not removed by current treatments at their administered doses. New chemotherapeutics are needed which can remove CSCs alongside bulk tumour cells at safe doses.

A promising strategy to eradicate entire tumours, including CSCs, is immunogenic cell death (ICD). ICD is a mode of cell death which stimulates the immune system to further remove cancerous cells. A CSC-active ICD agent may be able to directly eradicate bulk breast cancer cells and CSCs and stimulate the immune system to remove residual cells. ICD occurs following oxidative stress of the endoplasmic reticulum (ER). Redox active copper(II) complexes have been shown to elevate intracellular ROS levels. If directed to the ER, copper(II) complexes may be capable of oxidatively stressing the ER, triggering ICD.

This project aims to develop novel copper(II) complexes which can target the ER, elevate intracellular ROS levels and induce ICD in breast CSCs. This thesis describes the synthesis, characterisation, and evaluation of the biophysical and anti-CSC properties of the complexes.

Novel copper(II) complexes with improved stability and potency compared to previous anti-breast CSC copper(II) complexes were developed. Complexes 4 and 17, containing 4,7-diphenyl-1,10-phenanthroline, were found to induce ICD in breast CSCs following oxidate ER stress. Complex 15, containing 3,4,7,8-tetramethyl-1,10-phenanthroline, was found to induce autophagic cell death in breast CSCs. Complex 13, containing 1,10-phenanthroline, was found to induce apoptosis in breast CSCs. The phenanthroline ligand present in these complexes determines the mode of breast CSC death. Complexes 19-23 and 26, containing sulphonamide-functionalised terpyridine ligands, were found to increase intracellular ROS levels, partially induce ER stress, and kill breast CSCs via caspase independent apoptosis.