Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or nonspecific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase–drug–DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. It may also be possible to design catalytic inhibitors of topoisomerases by targeting certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.
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January 2018
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Cover Image
In this issue of the Biochemical Journal, Dukic et al. report that ezrin-anchored PKA phosphorylates serine 369 and 373 on connexin 43 to enhance gap junction assembly, communication, and cell fusion. The cover image, taken from Figure 6 in the article, shows HEK293 cells transfected with mammalian expression vectors encoding siRNA-resistant Cx43 without ability to bind to ezrin and with a phosphomimicking S to D substitution in residue 369.
Review Article|
January 23 2018
Topoisomerases as anticancer targets
Justine L. Delgado;
Justine L. Delgado
*
1Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, 115 S Grand Ave., S321 Pharmacy Building, Iowa City, IA 52242, U.S.A.
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Chao-Ming Hsieh;
Chao-Ming Hsieh
*
2Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan
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Nei-Li Chan;
Nei-Li Chan
2Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan
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Hiroshi Hiasa
3Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, U.S.A.
Correspondence: Hiroshi Hiasa (hiasa001@umn.edu)
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Publisher: Portland Press Ltd
Received:
October 06 2017
Revision Received:
December 14 2017
Accepted:
December 21 2017
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem J (2018) 475 (2): 373–398.
Article history
Received:
October 06 2017
Revision Received:
December 14 2017
Accepted:
December 21 2017
Citation
Justine L. Delgado, Chao-Ming Hsieh, Nei-Li Chan, Hiroshi Hiasa; Topoisomerases as anticancer targets. Biochem J 31 January 2018; 475 (2): 373–398. doi: https://doi.org/10.1042/BCJ20160583
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