nk314 and Leukemia--T-Cell

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.

Topics: Adult; Animals; Antigens, Neoplasm; Antineoplastic Agents; Apoptosis; Cell Proliferation; Cells, Cultured; DNA Breaks, Double-Stranded; DNA Repair; DNA Topoisomerases, Type II; DNA-Activated Protein Kinase; DNA-Binding Proteins; Enzyme Inhibitors; Humans; Jurkat Cells; Leukemia, T-Cell; Mice; Mice, SCID; Molecular Targeted Therapy; Phenanthrenes; Radiation, Ionizing; Xenograft Model Antitumor Assays