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1'-Acetoxychavicol Acetate Is a Novel Nuclear Factor B Inhibitor with Significant Activity against Multiple Myeloma In vitro and In vivo

¹ Division of Hematology, Department of Internal Medicine and ² Pathology, Keio University School of Medicine, Tokyo, Japan; ³ Institute of Biological Science, Science University of Tokyo, Chiba, Japan; and ⁴ Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan

Requests for reprints: Masahiro Kizaki, Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Phone: 81-3-5363-3785; Fax: 81-3-3353-3515; E-mail: makizaki{at}sc.itc.keio.ac.jp.

1'-Acetoxychavicol acetate (ACA) is a component of a traditional Asian condiment obtained from the rhizomes of the commonly used ethno-medicinal plant Languas galanga. Here, we show for the first time that ACA dramatically inhibits the cellular growth of human myeloma cells via the inhibition of nuclear factor B (NF-B) activity. In myeloma cells, cultivation with ACA induced G₀-G₁ phase cell cycle arrest, followed by apoptosis. Treatment with ACA induced caspase 3, 9, and 8 activities, suggesting that ACA-induced apoptosis in myeloma cells mediates both mitochondrial- and Fas-dependent pathways. Furthermore, we showed that ACA significantly inhibits the serine phosphorylation and degradation of IB. ACA rapidly decreased the nuclear expression of NF-B, but increased the accumulation of cytosol NF-B in RPMI8226 cells, indicating that ACA inhibits the translocation of NF-B from the cytosol to the nucleus. To evaluate the effects of ACA in vivo, RPMI8226-transplanted NOD/SCID mice were treated with ACA. Tumor weight significantly decreased in the ACA-treated mice compared with the control mice. In conclusion, ACA has an inhibitory effect on NF-B, and induces the apoptosis of myeloma cells in vitro and in vivo. ACA, therefore, provides a new biologically based therapy for the treatment of multiple myeloma patients as a novel NF-B inhibitor.