Mitochondrial Medicine and Biology

Cancer cells are under increased intrinsic oxidative stress that leads to mitochondrial dysfuction. Research in the Filipovska laboratory dissects the oxidative stress pathways that are involved in the progression of tumourigenesis to find new targets for early detection and prognosis of cancer. Recent developments in understanding the central place of mitochondria as regulators of cell death have stimulated enormous interest in targeting mitochondria in new approaches to cancer chemotherapy. We use new drugs to target oxidative stress pathways and mitochondria in cells to aid the development of new chemotherapeutics.

Senior Research Staff

Dr Aleksandra Filipovska Head, Mitochondrial Medicine and Biology Research: mitochondrial dysfunction in cancer; thioredoxin proteins

Research Details

Antioxidant proteins in prostate cancer

There is considerable evidence that cancer cells are under increased intrinsic oxidative stress, partly due to oncogenic stimulation, increased metabolic activity and mitochondrial dysfunction. Tumourigenesis is stimulated by prolonged exposure to reactive oxygen (ROS), which signal cellular proliferation in an effort to restore normal cell growth. The excessive ROS production in cancer cells is an endogenous source of DNA-damaging agents that promote genetic instability and confer drug resistance. ROS also contribute to the redox disequilibrium and alter the cellular apoptotic response to anticancer agents. Consequently, antioxidant proteins with selenol- and thiol-active sites have altered expression and activity in cancer cells since they are most prone to oxidation. This implies that the maintenance of the cellular reducing environment is crucial and that these proteins play an important role in regulating the redox poise in the cell as well as in transcription, protein-DNA interactions and cell growth. The aim of this research project is to study antioxidant proteins such as thioredoxins that have impaired function in prostate cancer and identify novel substrates of these proteins. This will allow us to dissect the redox signaling pathways that are altered during the progression of prostate cancer and to find new targets for early detection and prognosis of prostate cancer. As part of this project we have identified an uncharacterized mitochondrial protein that is important for maintaining the mitochondrial membrane potential and cell survival.

Mitochondria as targets for chemotherapeutics

Recent developments in understanding the central place of mitochondria as a regulator of cell death have stimulated enormous interest in targeting mitochondria in new approaches to cancer chemotherapy. A major aim for this research is to overcome the two problems in cancer chemotherapy, drug resistance and the lack of selectivity of cancer drugs in differentiating between normal and tumour cells. A number of therapeutic strategies targeting mitochondria for cancer therapy have been described which include a variety of gold compounds (Au(I) and Au(III)). In my group we are using an exciting new approach to cancer chemotherapy that involves targeting mitochondrial thiol and selenol antioxidant proteins, which have altered function in cancer cells. We have been using lipophilic gold compounds synthesized by my collaborators, Prof Sue Berners-Price and Prof Murray Baker, as probes to study the importance of antioxidant proteins in cancer cells. This has led to the discovery that mitochondrial antioxidant proteins may be the critical targets responsible for the selective toxicity to cancer cells of this class of compounds. We are investigating the mechanism of selective antitumour activity of gold lipophilic compounds in cancer cells, which will enable us to identify gold compounds with optimal properties that selectively target mitochondrial antioxidant proteins in cancer cells. The aim is to develop novel and unique probes for the study of mitochondrial redox regulation in cells and aid the development of new chemotherapeutics.