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Nucleic Acids Research 2006 34(4):1148-1157; doi:10.1093/nar/gkj516
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Published online 16 February 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage

Catherine R. Barker, Anne V. McNamara, Stephen A. Rackstraw, David E. Nelson1, Mike R. White1, Alastair J. M. Watson and John R. Jenkins*

The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Division of Gastroenterology, School of Clinical Sciences, University of Liverpool Crown Street, Liverpool L69 3BX, UK 1Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, University of Liverpool Crown Street, Liverpool, L69 7ZB, UK

*To whom correspondence should be addressed at Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Department of Medicine, University of Liverpool, Liverpool L69 3BX, U.K. Tel: +44 151 794 6828; Fax: +44 151 794 6825; Email: john.jenkins{at}liverpool.ac.uk

Received October 7, 2005. Revised November 23, 2005. Accepted February 1, 2006.

Topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and meiosis and is a highly attractive target for chemotherapeutic agents. We have identified previously topoisomerase II and heat shock protein 90 (Hsp90) as part of a complex. In this paper we demonstrate that drug combinations targeting these two enzymes cause a synergistic increase in apoptosis. The objective of our study was to identify the mode of cell killing and the mechanism behind the increase in topoisomerase II mediated DNA damage. Importantly we demonstrate that Hsp90 inhibition results in an increased topoiosmerase II activity but not degradation of topoisomerase II and it is this, in the presence of a topoisomerase II poison that causes the increase in cell death. Our results suggest a novel mechanism of action where the inhibition of Hsp90 disrupts the Hsp90–topoisomerase II interaction leading to an increase in and activation of unbound topoisomerase II, which, in the presence of a topoisomerase II poison leads to the formation of an increased number of cleavable complexes ultimately resulting in rise in DNA damage and a subsequent increase cell death.


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