Mechanism of action of TOP2-directed anticancer drugs

TOP2靶向抗癌药物的作用机制

• 批准号: 7006957
• 负责人: LEROY F LIU
• 金额: $ 28.02万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-10 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006957
• 关键词: DNA damage; DNA topoisomerases; antineoplastics; biological signal transduction; carcinogenesis; cell death; genetically modified animals; laboratory mouse; neoplasm /cancer pharmacology; peptidases; pharmacokinetics; ubiquitin

DESCRIPTION (provided by applicant): The long-term goal of this application is to determine the mechanism of action of topoisomerase II (TOP2)-directed anticancer drugs. In addition to their antitumor activities, TOP2-directed anticancer drugs;uch as VP-16 have been associated with the development of therapy-related acute myelogenous leukaemia (AML). Indeed, our preliminary studies have shown that VP-16 behaves as a stage I tumor promoter in the mouse skin carcinogenesis model. TOP2-directed anticancer drugs are known to trap both TOP2 isozymes, TOP2 alpha and TOP2 beta, into their respective covalent complexes with DNA known as cleavable or cleavage complexes. These two TOP2 isozymes are regulated differently during the cell cycle and most likely perform different functions. However, the differential roles of these two TOP2 isozymes in the antitumor and carcinogenic activities of TOP-directed anticancer drugs remain unclear. Our recent studies have demonstrated that TOP2 beta but not TOP2 alpha cleavage complexes induced by the TOP2-directed anti-cancer drug, VP-16, trigger ubiquitin/26S proteasome-dependent degradation of TOP2 beta (TOP2beta down-regulation). This is the first demonstration of a TOP2 isozyme-specific cellular response to TOP2-directed anticancer drugs. TOP2beta down-regulation is dependent on RNA transcription but not new protein synthesis. Concurrent with TOP2 beta down-regulation, the large subunit of RNA polymerase II, but not other proteins, is also degraded by 26S proteasome. These and other results have suggested that a ubiquitin/26S proteasome pathway(s) is activated locally in the vicinity of the arrested RNA polymerase elongation complexes, leading to the degradation of the TOP2 beta-DNA covalent complex. We further hypothesize that degradation of the TOP2 beta-DNA covalent complex results in exposure of theTOP2-concealed double-strand breaks, which could contribute to both tumor cell death and DNA sequence rearrangements/carcinogenesis. Elucidation of the differential cellular responses to TOP2 cleavage complexes formed by TOP2 isozymes may form the foundation for future development of TOP2 isozyme-specific anticancer drugs. The objective of the current application is to characterize the ubiquitin/26S proteasome pathway induced by TOP2-directed anticancer drugs and to explore the biological consequences of TOP2 beta down-regulation in tumor cell death and carcinogenesis.

描述（由申请人提供）：本申请的长期目标是确定拓扑异构酶II（TOP2）指导的抗癌药物的作用机理。除了它们的抗肿瘤活性外，TOP2定向的抗癌药物; UCH为VP-16与治疗相关的急性急性骨髓性白血病（AML）的发展有关。实际上，我们的初步研究表明，VP-16在小鼠皮肤致癌模型中表现为I期肿瘤启动子。众所周知，TOP2定向的抗癌药物可将TOP2同工酶（Top2 alpha and top2 beta）捕获到其各自的共价复合物中，其DNA被称为裂解或裂解复合物。这两个TOP2同工酶在细胞周期中的调节不同，并且很可能执行不同的功能。然而，这两个TOP2同工酶在替补药物的抗肿瘤和致癌活性中的差异作用尚不清楚。我们最近的研究表明，TOP2β，但不是由TOP2定向的抗癌药VP-16引起的TOP2α裂解复合物，触发泛素/26S蛋白酶体依赖性蛋白酶体依赖性top2 beta（top2beta下调）。这是TOP2同工酶特异性细胞对TOP2定向抗癌药物的首次演示。 TOP2BETA下调取决于RNA转录，而不是新的蛋白质合成。与TOP2β下调的同时，RNA聚合酶II的大量亚基，但没有其他蛋白质，也被26S蛋白酶体降解。这些和其他结果表明，泛素/26S蛋白酶体途径在被捕的RNA聚合酶伸长酶伸长率复合物附近局部激活，从而导致Top2β-DNA共价复合物的降解。我们进一步假设Top2β-DNA共价复合物的降解会导致暴露于thetop2共核的双链断裂，这可能导致肿瘤细胞死亡和DNA序列重排/癌变。阐明TOP2同工酶形成的TOP2裂解络合物的差分细胞反应可能构成TOP2同工酶特异性抗癌药物的未来发展的基础。当前应用的目的是表征由TOP2定向抗癌药引起的泛素/26S蛋白酶体途径，并探索肿瘤细胞死亡和致癌作用中TOP2β下调的生物学后果。