Topoisomerases as anticancer targets
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 respon...
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| Vydané v: | Biochemical journal Ročník 475; číslo 2; s. 373 |
|---|---|
| Hlavní autori: | , , , |
| Médium: | Journal Article |
| Jazyk: | English |
| Vydavateľské údaje: |
England
23.01.2018
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| Predmet: | |
| ISSN: | 1470-8728, 1470-8728 |
| On-line prístup: | Zistit podrobnosti o prístupe |
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| Abstract | 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. |
|---|---|
| AbstractList | 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.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. 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. |
| Author | Delgado, Justine L Chan, Nei-Li Hsieh, Chao-Ming Hiasa, Hiroshi |
| Author_xml | – sequence: 1 givenname: Justine L surname: Delgado fullname: Delgado, Justine L organization: Division 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 – sequence: 2 givenname: Chao-Ming surname: Hsieh fullname: Hsieh, Chao-Ming organization: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan – sequence: 3 givenname: Nei-Li surname: Chan fullname: Chan, Nei-Li organization: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan – sequence: 4 givenname: Hiroshi surname: Hiasa fullname: Hiasa, Hiroshi email: hiasa001@umn.edu organization: Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, U.S.A. hiasa001@umn.edu |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29363591$$D View this record in MEDLINE/PubMed |
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| Snippet | Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However,... |
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| SubjectTerms | Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Catalytic Domain DNA - chemistry DNA - genetics DNA - metabolism DNA Breaks, Double-Stranded DNA Topoisomerases, Type II - chemistry DNA Topoisomerases, Type II - genetics DNA Topoisomerases, Type II - metabolism DNA, Neoplasm - chemistry DNA, Neoplasm - genetics DNA, Neoplasm - metabolism Drug Design Gene Expression Humans Molecular Docking Simulation Molecular Targeted Therapy - methods Neoplasms - drug therapy Neoplasms - enzymology Neoplasms - genetics Neoplasms - pathology Protein Structure, Secondary Structure-Activity Relationship Topoisomerase Inhibitors - chemistry Topoisomerase Inhibitors - pharmacology |
| Title | Topoisomerases as anticancer targets |
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| Volume | 475 |
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