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The topoisomerase II–Hsp90 complex: A new chemotherapeutic target?
Author(s) -
Barker Catherine R.,
Hamlett Jane,
Pennington Stephen R.,
Burrows Francis,
Lundgren Karen,
Lough Rachel,
Watson Alastair J.M.,
Jenkins John R.
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21717
Subject(s) - topoisomerase , geldanamycin , etoposide , heat shock protein , topoisomerase inhibitor , hsp90 , biology , mitoxantrone , immunoprecipitation , microbiology and biotechnology , chemistry , biochemistry , in vitro , genetics , gene , chemotherapy
The modulation of DNA topology by topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and has thus become a highly attractive target for chemotherapeutic drugs. However, these drugs are highly toxic, and so new approaches are required. One such strategy is to target topoisomerase II‐interacting proteins. Here we report the identification of potential topoisomerase II‐associated proteins using immunoprecipitation, followed by 1‐D and 2‐D gel electrophoresis and MALDI‐TOF mass spectrometry. A total of 23 proteins were identified and, of these, 17 were further validated as topoisomerase IIα‐associated proteins by coimmunoprecipitation and Western blot. Six of the interacting proteins were cellular chaperones, including 3 members of the heat shock protein‐90 (Hsp90) family, and so the effect of Hsp90 modulation on the antitumor activity of topoisomerase II drugs was tested using the sulforhodamine B assay, clonogenic assays and a xenograft model. The Hsp90 inhibitors geldanamycin, 17‐AAG (17‐allylamino‐17‐demethoxygeldanamycin) and radicicol significantly enhanced the activity of the topoisomerase II poisons etoposide and mitoxantrone in vitro and in vivo. Thus, our method of identifying topoisomerase II‐interacting proteins appears to be effective, and at least 1 novel topoisomerase IIα‐associated protein, Hsp90, may represent a valid drug target in the context of topoisomerase II‐directed chemotherapy. © 2005 Wiley‐Liss, Inc.