NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase II alpha and DNA-dependent protein kinase

作者：Hisatomi Takashi; Sueoka Aragane Naoko; Sato Akemi; Tomimasu Rika; Ide Masaru; Kurimasa Akihiro; Okamoto Kazuya; Kimura Shinya; Sueoka Eisaburo^*

来源：Blood, 2011, 117(13): 3575-3584.

DOI：10.1182/blood-2010-02-270439

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)

• 出版日期2011-3-31