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Research ArticleArticle

Salicylate, a Catalytic Inhibitor of Topoisomerase II, Inhibits DNA Cleavage and Is Selective for the α Isoform

Jason T. Bau, Zhili Kang, Caroline A. Austin and Ebba U. Kurz
Molecular Pharmacology February 2014, 85 (2) 198-207; DOI: https://doi.org/10.1124/mol.113.088963
Jason T. Bau
Southern Alberta Cancer Research Institute and Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (J.T.B., Z.K., E.U.K.); and Institute for Cellular and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom (C.A.A.)
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Zhili Kang
Southern Alberta Cancer Research Institute and Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (J.T.B., Z.K., E.U.K.); and Institute for Cellular and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom (C.A.A.)
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Caroline A. Austin
Southern Alberta Cancer Research Institute and Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (J.T.B., Z.K., E.U.K.); and Institute for Cellular and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom (C.A.A.)
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Ebba U. Kurz
Southern Alberta Cancer Research Institute and Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (J.T.B., Z.K., E.U.K.); and Institute for Cellular and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom (C.A.A.)
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Abstract

Topoisomerase II (topo II) is a ubiquitous enzyme that is essential for cell survival through its role in regulating DNA topology and chromatid separation. Topo II can be poisoned by common chemotherapeutics (such as doxorubicin and etoposide), leading to the accumulation of cytotoxic enzyme-linked DNA double-stranded breaks. In contrast, nonbreak-inducing topo II catalytic inhibitors have also been described and have more limited use in clinical chemotherapy. These agents, however, may alter the efficacy of regimens incorporating topo II poisons. We previously identified salicylate, the primary metabolite of aspirin, as a novel catalytic inhibitor of topo II. We have now determined the mechanism by which salicylate inhibits topo II. As catalytic inhibitors can act at a number of steps in the topo II catalytic cycle, we used multiple independent, biochemical approaches to interrogate the catalytic cycle. Furthermore, as mammalian cells express two isoforms of topo II (α and β), we examined whether salicylate was isoform selective. Our results demonstrate that salicylate is unable to intercalate DNA, and does not prevent enzyme–DNA interaction, nor does it promote stabilization of topo IIα in closed clamps on DNA. Although salicylate decreased topo IIα ATPase activity in a dose-dependent noncompetitive manner, this was secondary to salicylate-mediated inhibition of DNA cleavage. Surprisingly, comparison of salicylate’s effects using purified human topo IIα and topo IIβ revealed that salicylate selectively inhibits the α isoform. These findings provide a definitive mechanism for salicylate-mediated inhibition of topo IIα and provide support for further studies determining the basis for its isoform selectivity.

Footnotes

    • Received August 2, 2013.
    • Accepted November 12, 2013.
  • This work was supported by a research grant from the Canadian Breast Cancer Foundation (Prairies/NWT Division) (to E.U.K.). J.T.B. was supported by Canada Graduate Studentship from the Natural Sciences and Engineering Research Council and is currently supported by a Queen Elizabeth II Graduate Scholarship.

  • dx.doi.org/10.1124/mol.113.088963.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 85 (2)
Molecular Pharmacology
Vol. 85, Issue 2
1 Feb 2014
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Research ArticleArticle

Salicylate Inhibits Topoisomerase IΙα DNA Cleavage

Jason T. Bau, Zhili Kang, Caroline A. Austin and Ebba U. Kurz
Molecular Pharmacology February 1, 2014, 85 (2) 198-207; DOI: https://doi.org/10.1124/mol.113.088963

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Research ArticleArticle

Salicylate Inhibits Topoisomerase IΙα DNA Cleavage

Jason T. Bau, Zhili Kang, Caroline A. Austin and Ebba U. Kurz
Molecular Pharmacology February 1, 2014, 85 (2) 198-207; DOI: https://doi.org/10.1124/mol.113.088963
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