Journal article

Studies of Glutathione Transferase P1-1 Bound to a Platinum(IV)-Based Anticancer Compound Reveal the Molecular Basis of Its Activation

Lorien J Parker, Louis C Italiano, Craig J Morton, Nancy C Hancock, David B Ascher, Jade B Aitken, Hugh H Harris, Pablo Campomanes, Ursula Rothlisberger, Anastasia De Luca, Mario Lo Bello, Wee Han Ang, Paul J Dyson, Michael W Parker

Chemistry - A European Journal | WILEY-V C H VERLAG GMBH | Published : 2011

Abstract

Platinum-based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S-transferase (GST P1-1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA-CPT), a trans-Pt(IV) carboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA-CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cispla..

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Grants

Awarded by Fundacion Espanola para la Ciencia y la Tecnologia (FECYT)


Awarded by Swiss National Science Foundation


Funding Acknowledgements

We thank Mike Gorman and Guido Hansen for advice and encouragement. We also thank the GM/CA staff for their help at the Advanced Photon Source. This work was supported by the Australian Synchrotron Research Program, which is funded by the Commonwealth of Australia under the Major National Research Facilities Program. Use of the Advanced Photon Source was supported by the U.S. DOE, Basic Energy Sciences, Office of Energy Research. This work was supported by grants from the Australian Research Council (ARC) to M. W. P. and H. H. H., the Australian Cancer Research Foundation to M. W. P. and from PRIN 2008 to M. L. B. P. C. thanks the Ministerio de Educacion y Ciencia (MEC) and Fundacion Espanola para la Ciencia y la Tecnologia (FECYT) for financial support (ref. [2007]-0486). The CSCS (Manno, Switzerland) is acknowledged for providing access to its supercomputing facilities. Support from the Swiss National Science Foundation (Grant No. 200020-125173/1) is also gratefully acknowledged. L.J.P was supported by a National Health and Medical Research Council of Australia (NHMRC), Dora Lush Scholarship and an International Centre for Diffraction Data Crystallography Scholarship. D. B. A was an Australian Postgraduate Award Scholar and a recipient of a St. Vincent's Institute Foundation Scholarship sponsored by Colin North and Major Engineering. L. C. I. was supported by a St. Vincent's Institute Foundation award. H. H. H is an ARC Queen Elizabeth II Fellow and M. W. P. is an ARC Federation Fellow and NHMRC Honorary Fellow.