Proteasomal inhibition potentiates drugs targeting DNA topoisomerase II.
Proteasomal inhibition potentiates drugs targeting DNA topoisomerase II.
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DOI：
10.1016/j.bcp.2015.12.015
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发表时间：
2016-03-01
影响因子：
5.8
通讯作者：
Austin, Caroline A.
中科院分区：
文献类型：
--
作者：
Lee, Ka C.;Bramley, Rebecca L.;Cowell, Ian G.;Jackson, Graham H.;Austin, Caroline A.
DNA拓扑异构酶II（TOP2）的反应机制涉及共价双链断裂中间体，其中酶通过5′-磷酸酪氨酰键与DNA偶联。这种通常短暂的酶桥断裂被药物稳定，如米托蒽醌、mAMSA、依托泊苷、阿霉素、表阿霉素和伊达比星，它们被称为TOP2毒物。蛋白酶体清除拓扑异构酶II参与了这些病变的修复。在K562细胞中，用MG 132抑制蛋白酶体显著增强了这六种靶向拓扑异构酶II的药物的生长抑制作用，并且观察到米托蒽醌的增强作用最高。MG 132在具有不同水平的TOP 2A或TOP 2B的三种Nalm 6细胞系中也显示出米托蒽醌的最大增强作用。临床使用的蛋白酶体抑制剂PS341（Velcade）也可增强米托蒽醌。我们还表明，在K562细胞中用MG 132抑制蛋白酶体降低了从DNA中去除米托蒽醌或依托泊苷稳定的拓扑异构酶复合物的速率，这表明通过蛋白酶体抑制增强拓扑异构酶II药物的可能机制。
The reaction mechanism of DNA topoisomerase II (TOP2) involves a covalent double-strand break intermediate in which the enzyme is coupled to DNA via a 5′-phosphotyrosyl bond. This normally transient enzyme-bridged break is stabilised by drugs such as mitoxantrone, mAMSA, etoposide, doxorubicin, epirubicin and idarubicin, which are referred to as TOP2 poisons. Removal of topoisomerase II by the proteasome is involved in the repair of these lesions. In K562 cells, inhibiting the proteasome with MG132 significantly potentiated the growth inhibition by these six drugs that target topoisomerase II, and the highest level of potentiation was observed with mitoxantrone. Mitoxantrone also showed the greatest potentiation by MG132 in three Nalm 6 cell lines with differing levels of TOP2A or TOP2B. Mitoxantrone was also potentiated by the clinically used proteasome inhibitor PS341 (Velcade). We have also shown that proteasome inhibition with MG132 in K562 cells reduces the rate of removal of mitoxantrone or etoposide stabilised topoisomerase complexes from DNA, suggesting a possible mechanism for the potentiation of topoisomerase II drugs by proteasomal inhibition.
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影响因子：
3
作者：
Errington, F;Willmore, E;Austin, CA
通讯作者：
Austin, CA
影响因子：
5.8
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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