Japonicone A Suppresses Growth of Burkitt Lymphoma Cells through Its Effect on NF-κB

Purpose: NF-kappa B, a transcriptional regulator of diverse genes involved in cell survival, proliferation, adhesion, and apoptosis, has been implicated in various malignancies. We discovered a potent natural NF-kappa B inhibitor, Japonicone A, from the traditional herb Inula japonica Thunb, evaluated its preclinical pharmacology and therapeutic activity, and investigated the underlying mechanisms of action for its antitumor activity. Experimental Design: Various types of cancer and normal cells were exposed to Japonicone A for cytotoxicity screening, followed by determination of cell apoptosis and cell-cycle arrest. Western blotting, immunostaining, and gene reporter assay were used to analyze NF-kappa B activity. Two xenograft models were used for therapeutic efficacy evaluation. Results: Japonicone A killed cancer cells but had low cytotoxicity to normal cells. Burkitt lymphoma cells were particularly sensitive. Japonicone A inhibited the growth and proliferation of Raji, BJAB, and NAMALWA lymphoma cells and resulted in G(2)-M phase arrest and apoptosis. Furthermore, exposure of cells to Japonicone A caused inactivation of the TNF-alpha-TAK1-IKK-NF-kappa B axis and inhibition of TNF alpha-stimulated NF-kappa B activity and nuclear translocation, followed by downregulation of NF-kappa B target genes involved in cell apoptosis (Bcl-2, Bcl-xL, XIAP, TRAF2) and in the cell cycle and growth (cyclin D, c-Myc). Moreover, Japonicone A inhibited local growth and dissemination of cancer cells to multiple organs in vivo. Conclusion: Japonicone A exerts significant anticancer effects on Burkitt lymphoma cells in vitro and in vivo through targeting of the NF-kB signaling cascade. These results highlight the potential of Japonicone A as a chemotherapeutic agent and warrant its development as a therapy for lymphomas. (c) 2013 AACR.