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

DOI PDF PubMed 被引用文献4件 参考文献53件
  • Takashi Hisatomi
    Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;
  • Naoko Sueoka-Aragane
    Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;
  • Akemi Sato
    Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;
  • Rika Tomimasu
    Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;
  • Masaru Ide
    Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;
  • Akihiro Kurimasa
    Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Tottori Japan;
  • Kazuya Okamoto
    Pharmaceutical Research Laboratories, Nippon Kayaku Co, Ltd, Tokyo, Japan; and
  • Shinya Kimura
    Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;
  • Eisaburo Sueoka
    Department of Transfusion Medicine, Saga University Hospital, Saga, Japan

書誌事項

公開日
2011-03-31
資源種別
journal article
DOI
  • 10.1182/blood-2010-02-270439
公開者
American Society of Hematology

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説明

<jats:title>Abstract</jats:title> <jats:p>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 IIα (Top2α), 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 Top2α, NK314 induced degradation 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. A DNA-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 Top2α 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.</jats:p>

収録刊行物

  • Blood

    Blood 117 (13), 3575-3584, 2011-03-31

    American Society of Hematology

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