Japonicone A suppresses growth of Burkitt lymphoma cells through its effect on NF-κB.

Abstract

PURPOSE:

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 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-κB 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 G2-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 in vivo.

CONCLUSION:

Japonicone A exerts significant anticancer effects on Burkitt lymphoma cells in vitro and in vivo 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.

• Authors: Xiaoguang Li, Xinying Yang, Yanling Liu, Nuoxi Gong, Wenbo Yao, Peizhan Chen, Jiangjiang Qin, Huizi Jin, Jingquan Li, Ruiai Chu, Lei Shan, Ruiwen Zhang, Weidong Zhang, Hui Wang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 11 Pg. 2917-28 (Jun 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23620411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR

Chemical References

• Antineoplastic Agents, Phytogenic
• NF-kappa B
• Sesquiterpenes, Eudesmane
• Sesquiterpenes, Guaiane
• Tumor Necrosis Factor-alpha
• japonicone A
• I-kappa B Kinase
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7

Topics

• Animals
• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacology, toxicity)
• Apoptosis (drug effects, genetics)
• Burkitt Lymphoma (drug therapy, genetics, metabolism)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cell Proliferation (drug effects)
• Enzyme Activation (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• I-kappa B Kinase (metabolism)
• MAP Kinase Kinase Kinases (metabolism)
• Mice
• NF-kappa B (metabolism)
• Protein Transport
• Sesquiterpenes, Eudesmane (administration & dosage, pharmacology, toxicity)
• Sesquiterpenes, Guaiane (administration & dosage, pharmacology, toxicity)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (pharmacology)
• Xenograft Model Antitumor Assays