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Impact of metal-based anticancer therapies on endogenous metal ion homeostasis

Principal Supervisor: Dr James P. C. CoverdaleLink opens in a new window

Co-supervisor: Dr Claudia A. Blindauer

PhD project title: Impact of metal-based anticancer therapies on endogenous metal ion homeostasis

University of Registration: University of Birmingham


Project outline:

Background: Metals are essential to life. Unlike organic biomolecules, metals cannot be synthesised or degraded in cells, and so the strict regulation of metal homeostasis (for example modulation of influx/efflux, compartmentalisation, and speciation) is critical to achieve correct cellular function. For example, Fe plays a role regulated in cell death pathways (e.g., ferroptosis – a cell death pathway which is mediated by iron dependent lipid peroxidation), while Fe dyshomeostasis is closely related to the occurrence and development of tumours.[1]

Metals are also present in pharmaceuticals: platinum anticancer agents can be found in around half of all chemotherapy plans, and promising anticancer therapies based on other xenobiotic metal ions (e.g., Ru, Os, Ir) are currently in development.[2] The drug development pathway for new metal-based therapeutics often explores the accumulation of the xenobiotic metal in cells in order to elucidate cellular influx and efflux mechanism(s) and cellular distribution, but consideration is seldom given to how metallodrugs might impact endogenous metal ion (e.g., Cu, Fe, and Zn) homeostasis – elements that are not only essential to life, but also prevalent factors in disease progression. Many metal-based therapies also target cellular redox processes/balance, often by generating reactive oxygen species (ROS) and/or targeting mitochondrial function. The cellular redox balance is intricately linked to endogenous metal biology; for example, Cu and Zn are co-factors of Cu/Zn superoxide dismutase, an enzyme which detoxifies ROS generated by the mitochondrial electron transport chain. Cu also has an indirect role on mitochondrial function, related to mitochondrial Fe uptake since Cu is a co-factor of ferroxidases.[3] In fact, Cu chelators are currently being evaluated for anticancer applications.[4] It is thus clear that there are multiple links between the mode of action of metallodrugs and the metabolism of endogenous metals, but despite this, little consideration has been given as to how endogenous metal ion homeostasis is impacted by xenobiotic drugs.

Objectives: This project will explore the impact of xenobiotic anticancer drugs on endogenous metal ion (e.g., Fe, Cu, Zn) homeostasis. Specifically, the project will develop new and existing bioanalytical and metalloproteomic techniques to quantify changes in intracellular metal ion concentrations, distributions, and speciation. In addition, mathematical and statistical models will be established to describe experimental data.

Methods: This highly interdisciplinary project will provide the student with laboratory training in a variety of methods, ranging from cellular biology to analytical chemistry. Using commercially available and clinically relevant metallodrugs, this project will investigate the time-dependent and concentration-dependent response of intracellular endogenous metal ions to xenobiotic metallodrugs. This will be achieved using acidic digestion of treated cell pellets and fractionated cell lysates, followed by metal quantitation using elemental analysis (ICP-MS). The project will build upon previous work by both research groups to develop effective hyphenated chromatographic techniques (LC-ICP-MS), fluorescence-based assays and proteomic methods to probe changes in endogenous metal ion and metalloprotein speciation.[5]

The Coverdale Group (University of Birmingham) will provide expertise in pharmaceutical biology and early-stage drug development, including all cell culture carried out during the project.[6-7] The Blindauer Group (University of Warwick) will bring expertise in inorganic and analytical chemistry to the project, as well as extensive knowledge and experience in the field of metalloproteomics.[8-9]


References:

[1] Q. Guo, et al., Frontiers in Oncology, 2021, 11. [2] Anthony et al., Chemical Science, 2020, 11, 12888-12917 [3] L. M. Ruiz, et al., Frontiers in Molecular Biosciences, 2021, 8. [4] D. Ramchandani et al., Nature Communications, 2021, 12, 7311. [5] Coverdale et al., Metallomics, 2019, 11, 1805. [6] Coverdale et al., Chemical Communications, 2022, 58, 7384-7387. [7] Coverdale et al., Nature Chemistry, 2018, 10, 347–354. [8] Blindauer et al., Journal of Proteomics, 2022, 263, 104615. [9] Blindauer et al., Nature Chemical Biology, 2022, 18, 869–877.

 

BBSRC Strategic Research Priority: Integrated Understanding of Health – Pharmaceuticals

Techniques that will be undertaken during the project:

  • Human cell culture and related biochemical assays
  • Fluorescence-based assays (e.g., confocal microscopy)
  • Liquid chromatographic techniques (HPLC, FPLC)
  • Gel electrophoresis (SDS-PAGE, Native-PAGE)
  • Elemental analysis (ICP-OES / ICP-MS)
  • Mass spectrometry (ESI-MS)
  • Mathematical modelling


Contact: Dr James P. C. CoverdaleLink opens in a new window