A common cause of failure in cancer therapy is the development of tumour resistance to chemotherapy drugs. This occurs when tumour cells acquire mutations which confer the ability to evade or neutralise the chemotherapy drug in some way. New drugs are therefore required to help restore the effectiveness of existing chemotherapy agents.
This project will aim to discover novel compounds which reverse the resistance of cultured tumour cell-lines to some of the most commonly used chemotherapy drugs. We will focus primarily on screens of natural products derived from extracts of traditional medicines, since this approach has historically been the most successful route to the discovery of new drugs. Plants, in particular, are a productive source of compounds for drug discovery, since they have faced millennia of natural selection to synthesise chemicals that target specific pathways in insects and mammalian herbivores to prevent grazing. This concentrated resource of potentially useful molecules has enabled the discovery of many of the current mainstays of cancer therapy. By focusing particularly on plants with a history of safe oral use in man through use as traditional medicines, the project aims to maximise the potential for discovery of ‘hits’ with high activity and low toxicity.
In this project, a natural product library based on such plants will be screened to identify extracts with potential to reverse resistance to commonly used chemotherapy drugs, including alkylating agents, antimetabolites, anti-microtubule agents and topoisomerase inhibitors. The screens will be performed in vitro against a range of tumour cell-lines with established resistance to these drugs. Compounds responsible for activity in each extract will then be isolated using activity guided separation. This will involve separation of extracts by high performance liquid chromatography (HPLC), and compound identification by gas-chromatography mass-spectrometry (GC-MS) and metabolite database searching.
The major techniques involved in this project will include: in vitro mammalian cell culture, natural product library screening, cell viability assays, HPLC, GC-MS and metabolite database searching.
The expected outcome is the discovery of a range of compounds with low toxicity and the potential to reverse cellular mechanisms of chemotherapy resistance.
This project is self-funded. Details of studentships for which funding is available are selected by a competitive process and are advertised on our jobs website (View Website) as they become available.