Document Type

Theses, Ph.D

Disciplines

1.6 BIOLOGICAL SCIENCES

Abstract

With the increasing global cancer burden in recent years, there is an urgency to develop novel chemotherapeutic agents. Transition metal complexes represent an attractive class of candidates, owing to their unique electronic and stereochemical properties, as well as their capacity for ligand exchange, redox activity, and catalytic reactivity. These characteristics enable cellular signalling mechanisms that lead to tumour cell cytotoxicity via regulated cell death (RCD) mechanisms. The conventional RCD mechanisms of apoptosis and autophagy are attractive targets for the development of novel complexes because tumour cells evade apoptosis but use autophagy as a survival mechanism when under stress. Therefore, novel complexes that can activate or inhibit these RCD modalities respectively are attractive. However, in recent years there has been a surge in studies of new RCD modalities including those that are immune related which also need to be considered.

The research reported herein aims to evaluate the chemotherapeutic potential of a series of Copper(II), Manganese(II) and Silver(I) complexes, containing bridging dicarboxylate and 1,10-phenanthroline ligands; and to elucidate their individual modes of action. The use of both in vitro breast cancer (MCF-7) and non-tumorigenic breast epithelial (MCF-12A) cell lines, as well as the in vivo Galleria mellonella model was employed to elucidate their cytotoxic potential and underlying mechanisms of action. A combination of biochemical assays, flow cytometry, fluorescence imaging, survival analysis, and Raman microspectroscopy was employed to characterise their biological activity and identify regulated cell death (RCD) pathways involved. All metal-phenanthroline complexes demonstrated strong in vitro cytotoxicity, displaying greater potency towards breast cancer cells than the clinical therapeutic, cisplatin. Further ii probing of their mechanistic actions revealed distinct modes, ostensibly contingent on the type of metal centre incorporated into the complex. The Cu(II) complexes were found to induce cell death via the apoptotic pathway, engaging both the intrinsic and extrinsic pathway, with reactive oxygen species production contributing to their activity. The Mn(II) complex was multi-modal in its activity, in which ROS generation emerged as a major mechanism of action, underpinning the induction of both apoptotic and autophagic responses. The Ag(I) complexes presented with deviations from canonical cell death, leading to a hypothesis of the engagement of non-conventional RCD pathways. The application of Raman spectroscopy enabled the establishment of discrete spectral signatures for each complex, providing label-free validation of their divergent modes of action while uncovering additional molecular changes beyond the resolution of conventional assays.

This work builds cumulatively across three core studies: (i) an initial investigation of apoptosis as a classical RCD target for these metal complexes (Chapter 3 – https://doi.org/10.1007/s10534-025-00676-8), (ii) a subsequent exploration of autophagy and immune-related cell death responses (Chapter 4 – https://doi.org/10.1007/s10534-025-

00766-7), and (iii) an integrated mechanistic analysis supported by Raman spectral profiling (Chapter 5 – https://doi.org/10.1093/mtomcs/mfaf044).

Collectively, this work allowed for a comprehensive characterisation of the distinct modes of action elicited by Cu(II), Mn(II), and Ag(I) 1,10-phenanthroline complexes which are presented in chapter 6, with summary illustrations 6.1-6.3 for each complex respectively. This work provides evidence that these complexes are promising contenders as next-generation agents for cancer treatment, particularly breast cancer.

DOI

https://doi.org/10.21427/Z5PF-8K67

Creative Commons License

Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.

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