Self-funded PhD opportunities

Assessing the Potential Value of Repurposing Tricyclic Antidepressants (TCAs) for Treating Breast-to-brain Metastases

  • Application end date: Applications accepted all year round
  • Funding Availability: Self-funded PhD students only
  • Department: School of Pharmacy and Biomedical Sciences
  • PhD Supervisor: Dr Qian An

Breast cancer, along with lung cancer and melanoma, is one of the most aggressive human cancers in terms of developing brain metastasis, a condition associated with poor prognosis. This is mainly due to the presence of the blood–brain barrier (B-BB) that prevents a large number of antineoplastic agents from entering the brain. Previously published data have shown that tricyclic antidepressants (TCAs) can induce apoptosis by targeting mitochondria in glioma, metastatic melanoma, lung and colorectal cancer cells. To date, the anti-cancer activity of TCAs in breast cancer cells has not been reported.

This project aims to investigate activities of TCAs in breast cancer cells and evaluate potential drug repurposing for treating breast-to-brain metastases. A number of breast cancer cell lines and normal breast epithelial primary cultures will be exposed to amitriptyline, nortriptyline and norclomipramine (metabolic product of clomipramine in the brain). Cell viability, cytotoxicity and apoptosis activation will be analysed using the ApoTox-Glo Triplex Assay.

Drug activity in each cell line will be assessed by the inhibitory concentration 50 (IC50) value. The possible impact of TCAs on mitochondria will be investigated by analysing the activity of individual mitochondrial respiratory chain complexes, mitochondrial ROS (reactive oxygen species) levels and membrane potential. Additionally, mitochondrial DNA (mtDNA) variations will be investigated as potential biomarkers to assess drug sensitivity.

Bench fees (in GBP)

Year 1: £10000

Year 2: £11000

Year 3: £9500

Total: £30500