Topoisomerases as anticancer targets.
Topoisomerases as anticancer targets.
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DOI：
10.1042/bcj20160583
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发表时间：
2018-01-23
期刊：
影响因子：
--
通讯作者：
Hiasa H
中科院分区：
文献类型：
--
作者：
Delgado JL;Hsieh CM;Chan NL;Hiasa H
许多针对癌症类型的抗癌药物已经开发出来，并在癌症治疗的精准医学方面取得了重大进展。然而，传统或非特异性抗癌药物对于许多癌症患者的治疗仍然很重要，这些患者的癌症要么对癌症特异性抗癌药无效，要么对癌症特异性抗癌药产生抗药性。DNA拓扑异构酶，特别是IIA型拓扑异构酶，已被证明是抗癌和抗菌药物的治疗靶点。临床上成功的拓扑异构酶靶向抗癌药物通过拓扑异构酶中毒起作用，导致复制分叉停滞和双链断裂形成。不幸的是，这种独特的作用模式与继发性癌症和心脏毒性的发展有关。拓扑异构酶-药物-DNA三元复合体的结构揭示了拓扑异构酶毒物的确切结合部位和作用机理。该领域的最新进展表明，有可能设计针对异构体的人类拓扑异构酶II毒药，这种毒药可能被开发为更安全的抗癌药物。也有可能通过针对拓扑异构酶的某些非活性构象来设计这些酶的催化抑制剂。此外，各种新的细菌拓扑异构酶抑制剂和调节蛋白的鉴定可能会启发人们发现新的人类拓扑异构酶抑制剂。因此，拓扑异构酶仍然是抗癌药物的重要治疗靶点。
Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or non-specific 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 proven 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 a 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.