NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase
NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase
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DOI：
10.1182/blood-2010-02-270439
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发表时间：
2011-03-31
期刊：
影响因子：
20.3
通讯作者：
Sueoka, Eisaburo
中科院分区：
文献类型：
--
作者：
Hisatomi, Takashi;Sueoka-Aragane, Naoko;Sueoka, Eisaburo
成人T细胞白血病-淋巴瘤(ATL)是一种侵袭性疾病，标准化疗无法治愈。具有拓扑异构酶IIα(TOP2α)特异性抑制活性的新型抗癌药NK314对多种ATL细胞株(半数抑制浓度：23-70 nm)均有抑制作用，其抑制作用强于依托泊苷。NK314除了通过抑制TOP2α诱导DNA双链断裂外，还可引起DNA依赖蛋白激酶催化亚单位(DNA-PKcs)的降解，导致DNA双链断裂修复受损。NK314对M059J(DNA-PKcs缺失细胞株)和M059K(DNA-PKcs存在的细胞株)细胞的生长抑制作用相同，而依托泊苷对M059K细胞的生长抑制作用较弱。DNA-PK特异性抑制剂NU7026可增强依托泊苷对M059K和ATL细胞的抑制活性。这些结果表明，NK314是TOP2α和DNA-PK的双重抑制剂。由于ATL细胞表达大量的DNA-PKcs，NK314作为一种双分子靶向抗癌剂有望成为治疗ATL的潜在工具。(血。2011；117(13)：3575-3584)
Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease, incurable by standard chemotherapy. NK314, a new anticancer agent possessing inhibitory activity specific for topoisomerase II alpha (Top2 alpha), inhibited the growth of various ATL cell lines (50% inhibitory concentration: 23-70nM) with more potent activity than that of etoposide. In addition to the induction of DNA double-strand breaks by inhibition of Top2 alpha, NK314 induced degrada-tion of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), resulting in impaired DNA double-strand break repair. The contribution of DNA-PK to inhibition of cell growth was affirmed by the following results: NK314 inhibited cell growth of M059J (a DNA-PKcs-deficient cell line) and M059K (a cell line with DNA-PKcs present) with the same potency, whereas etoposide exhibited weak inhibition of cell growth with M059K cells. ADNA-PK specific inhibitor, NU7026, enhanced inhibitory activity of etoposide on M059K as well as on ATL cells. These results suggest that NK314 is a dual inhibitor of Top2 alpha and DNA-PK. Because ATL cells express a high amount of DNA-PKcs, NK314 as a dual molecular targeting anticancer agent is a potential therapeutic tool for treatment of ATL. (Blood. 2011;117(13):3575-3584)