Abstract
<div>Abstract<p><b>Purpose:</b> NF-κB, 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-κB inhibitor, Japonicone A, from the traditional herb <i>Inula japonica</i> Thunb, evaluated its preclinical pharmacology and therapeutic activity, and investigated the underlying mechanisms of action for its antitumor activity.</p><p><b>Experimental Design:</b> 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-κB activity. Two xenograft models were used for therapeutic efficacy evaluation.</p><p><b>Results:</b> 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<sub>2</sub>–M phase arrest and apoptosis. Furthermore, exposure of cells to Japonicone A caused inactivation of the TNF-α–TAK1–IKK-NF-κB axis and inhibition of TNF-α–stimulated NF-κB activity and nuclear translocation, followed by downregulation of NF-κB 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 <i>in vivo</i>.</p><p><b>Conclusion:</b> Japonicone A exerts significant anticancer effects on Burkitt lymphoma cells <i>in vitro</i> and <i>in vivo</i> through targeting of the NF-κB signaling cascade. These results highlight the potential of Japonicone A as a chemotherapeutic agent and warrant its development as a therapy for lymphomas. <i>Clin Cancer Res; 19(11); 2917–28. ©2013 AACR</i>.</p></div>
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