The Design of Gold-Based, Mitochondria-Targeted Chemotherapeutics

Susan J. Berners-Price; Aleksandra Filipovska

doi:10.1071/CH08175

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The Design of Gold-Based, Mitochondria-Targeted Chemotherapeutics

Susan J. Berners-Price ^A ^C and Aleksandra Filipovska ^A ^B ^C

+ Author Affiliations

- Author Affiliations

^A School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Perth, WA 6009, Australia.

^B Laboratory for Cancer Medicine, Western Australian Institute for Medical Research, University of Western Australia, Perth, WA 6000, Australia.

^C Corresponding authors. Email: sue.berners-price@uwa.edu.au; afilipov@waimr.uwa.edu.au

Sue Berners-Price received her Ph.D. in Chemistry from Birkbeck College, University of London, in 1985 and then moved to Australia as the Royal Society Florey Fellow. In 1990, she was appointed to a Lectureship at Griffith University, Brisbane, Australia and from 1992 to 1995 she was holder of an NHMRC R. Douglas Wright Award. In 2001, she was appointed to her current position as Professor of Biological Chemistry at the University of Western Australia, Perth, Australia. Her research interests are in the area of medicinal inorganic chemistry and she has a long-standing interest in the development of gold-based anticancer agents.

Aleksandra Filipovska received her B.Sc.(Hons) in 1998 and Ph.D. in 2002 from the University of Otago, New Zealand, focussing on the development of mitochondria-targeted antisense agents. In 2003, she was awarded a NZ Foundation for Research, Science and Technology Fellowship to work at the MRC Dunn Human Nutrition Unit in Cambridge, UK, where she developed mitochondria-targeted antioxidants to decrease oxidative damage and manipulate mitochondrial redox signalling in cells. In 2006, she relocated to Australia as an NHMRC Howard Florey Fellow and a group leader at the Western Australian Institute for Medical Research in Perth. Her research interests are in mitochondrial gene expression and in targeting molecules with biological function to mitochondria and cells.

Australian Journal of Chemistry 61(9) 661-668 https://doi.org/10.1071/CH08175
Submitted: 25 April 2008 Accepted: 4 July 2008 Published: 5 September 2008

Abstract

Recent developments in understanding the central place of mitochondria as regulators of programmed cell death have stimulated enormous interest in using them as targets for cancer chemotherapy. To overcome drug resistance and the lack of selectivity of cancer drugs in differentiating between normal and tumour cells, many strategies have been described in recent literature, including the use of delocalized lipophilic cations that selectively accumulate in tumour-cell mitochondria. Thioredoxin reductase, an enzyme involved in redox regulation and cell growth, has also emerged recently as an attractive drug target. Here we discuss the rationale for the design of lipophilic, cationic Au(i) phosphine complexes that are targeted to mitochondria of tumour cells and have potent and selective anticancer activity for cancer cells but not for normal cells. Our discovery that the thioredoxin system may be a critical target responsible for the selective toxicity provides a new strategy in the development of mitochondria-targeted chemotherapeutics.

Acknowledgements

The present work was supported in part by grants from the National Health and Medical Research Council, the Cancer Council of WA, and the Australian Research Council.

References

The Design of Gold-Based, Mitochondria-Targeted Chemotherapeutics

Abstract

Acknowledgements

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