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首页> 外文期刊>Biochemical Pharmacology >Anthracenedione-methionine conjugates are novel topoisomerase II-targeting anticancer agents with favorable drug resistance profiles
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Anthracenedione-methionine conjugates are novel topoisomerase II-targeting anticancer agents with favorable drug resistance profiles

机译：蒽二甲硫氨酸-蛋氨酸缀合物是靶向拓扑异构酶II的新型抗癌药物，具有良好的耐药性

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Structure-associated drug resistance and DNA-unwinding abilities have greatly limited the clinical usage of anthracenediones, including mitoxantrone (MX) and ametantrone (AT), which intercalate into DNA and induce topoisomerase II (TOP2)-mediated DNA break. We studied a series of 1,4-bis(2-amino-ethylamino) MX- and AT-amino acid conjugates (M/AACs) and showed that abilities in cancer cell killing correlate with the amounts of chromosomal DNA breaks induced by M/AACs. Notably, the 1,4-bis-L/l-methionine-conjugated MAC (L/LMet-MAC) exhibits DNA-breaking, cancer cell-killing and anti-tumor activities rivaling those of MX. Interestingly, l- and d-form Met-M/AACs unwind DNA poorly compared to MX and AT. The roles of the two human TOP2 isozymes (hTOP2α and 2β) in the L/LMet-MAC-induced DNA breakage and cancer cell-killing were suggested by the following observations: (i) M/AAC-induced DNA breakage, cytotoxicity and apoptosis are greatly reduced in various TOP2-deficient conditions; (ii) DNA breaks induced by MACs are highly reversible and effectively antagonized by the TOP2 catalytic inhibitors; (iii) MACs induced differential TOP2-mediated DNA cleavage in vitro using recombinant hTOP2α proteins and the formation of hTOP2α/βcc in the cell culture system. Interestingly, d-aa-conjugated MACs often caused a lower level in hTOP2-mediated DNA breaks and cell-killing than the corresponding l-form ones indicating a steric-specific effect of MACs. Together, our results suggest that both enzyme- and DNA-drug interactions might contribute to TOP2-targeting by M/AACs. Furthermore, Met-MACs are poor substrates for the MDR1 transporter. Therefore, L/LMet-MAC represents a promising class of TOP2-targeting drugs with favorable drug resistance profiles.
机译：与结构相关的抗药性和DNA释放能力极大地限制了蒽二酮的临床应用，包括米托蒽醌（MX）和金刚烷酮（AT），它们插入DNA中并诱导拓扑异构酶II（TOP2）介导的DNA断裂。我们研究了一系列的1,4-双（2-氨基-乙基氨基）MX-和AT-氨基酸结合物（M / AAC），并显示癌细胞杀伤能力与M /诱导的染色体DNA断裂量有关AAC。值得注意的是，与1,4-双-L / I-甲硫氨酸结合的MAC（L / LMet-MAC）具有与MX相当的DNA断裂，癌细胞杀伤和抗肿瘤活性。有趣的是，与MX和AT相比，L型和D型Met-M / AAC对DNA的解链作用很差。以下观察结果提示了两种人类TOP2同工酶（hTOP2α和2β）在L / LMet-MAC诱导的DNA断裂和癌细胞杀伤中的作用：（i）M / AAC诱导的DNA断裂，细胞毒性和凋亡在各种TOP2不足的条件下被大大降低; （ii）由MACs诱导的DNA断裂是高度可逆的，并被TOP2催化抑制剂有效地拮抗; （iii）MACs使用重组hTOP2α蛋白在体外诱导差异TOP2介导的DNA裂解，并在细胞培养系统中形成hTOP2α/βcc。有趣的是，d-aa缀合的MACs经常导致hTOP2介导的DNA断裂和细胞杀伤的水平低于相应的l型形式，表明MACs具有空间特异性作用。在一起，我们的结果表明，酶和DNA药物相互作用都可能有助于M / AAC靶向TOP2。此外，Met-MAC是MDR1转运蛋白的不良底物。因此，L / LMet-MAC代表具有良好耐药性的有前途的TOP2靶向药物。

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