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.
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.
Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
Takashi
T
Hisatomi
Naoko
N
Sueoka-Aragane
Akemi
A
Sato
Rika
R
Tomimasu
Masaru
M
Ide
Akihiro
A
Kurimasa
Kazuya
K
Okamoto
Shinya
S
Kimura
Eisaburo
E
Sueoka
D000328:Adult; D000818:Animals; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects; D004250:DNA Topoisomerases, Type II; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D011839:Radiation, Ionizing; D023041:Xenograft Model Antitumor Assays
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C522060:NK314; D010616:Phenanthrenes; D051747:DNA-Activated Protein Kinase; D004250:DNA Topoisomerases, Type II