phenanthrenes and Leukemia--T-Cell

We have studied the anti-cancer activities of antofine N-oxide isolated and purified from the medicinal plant Cynanchum vincetoxicum. Antofine N-oxide displayed a strong inhibitory effect on several solid tumor cell lines (glioblastoma, breast carcinoma and lung carcinoma) and on a T-cell leukemia cell line. Remarkably, its cytotoxic effect was considerably weaker in non-cancer cells. Antofine N-oxide was found to inhibit proliferation of the solid tumor cells whereas it caused apoptotic cell death in the leukemia cells. A microarray analysis after a short treatment revealed that the number of differentially expressed genes was considerably higher in solid tumor than in leukemia cells. Up-regulated genes in the three solid tumor cell lines include genes related to TNFα signaling, of which TNFα was among the most significantly induced. A functional analysis revealed that TNFR1 signaling was most likely activated in the solid tumor cells. The increased mRNA levels of several genes of this pathway (namely TNFα, TNFAIP3 and BIRC3) were confirmed by real-time quantitative PCR after different treatment durations. Finally a slight inhibition of NFκB-mediated transcription was observed in the same cells. Together our results suggest that inhibition of cell proliferation in solid tumor cells essentially occurs through TNFα signaling whereas this pathway is not activated in leukemia cells. Apoptotic cell death in the latter is induced by a distinct yet unknown pathway.

Topics: Alkaloids; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cynanchum; Gene Expression Profiling; Glioblastoma; Humans; Indolizines; Leukemia, T-Cell; Lung Neoplasms; NF-kappa B; Phenanthrenes; Receptors, Tumor Necrosis Factor, Type I; RNA, Messenger; Signal Transduction; Transcription, Genetic; Tumor Necrosis Factor-alpha

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