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¹ Department of Hematology, Kumamoto University School of Medicine, Kumamoto, Japan; and ² Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Tokyo, Japan

Requests for reprints: Hiroyuki Hata, Department of Hematology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Phone: 81-96-373-5156; Fax: 81-96-363-5265. E-mail: hata{at}kumamoto-u.ac.jp

Nuclear factor-B (NF-B) is constitutively activated in multiple myeloma cells. Several proteasome inhibitors have been shown to be effective against multiple myeloma and may act by inhibiting degradation of IB. Here, we examined the biological effects of a new type of NF-B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), which is reported to directly inhibit the cytoplasm-to-nucleus translocation of NF-B. A multiple myeloma cell line, 12PE, which is defective for IB protein, was utilized to determine if IB is concerned with the action of DHMEQ. Meanwhile, U266 was used as a multiple myeloma cell line with normal IB. A proteasome inhibitor, gliotoxin, which is an inhibitor of degradation of phosphorylated IB, failed to inhibit translocation of NF-B in 12PE. In contrast, DHMEQ equally inhibited translocation of NF-B to the nucleus and induced apoptosis to both multiple myeloma cell lines, suggesting that apoptosis resulting from DHMEQ is IB independent. DHMEQ also induced apoptosis in freshly isolated multiple myeloma cells. After DHMEQ treatment, cleavage of caspase-3 and down-regulation of cyclin D1 were observed in both cell lines. In addition, administration of DHMEQ resulted in a significant reduction in tumor volume in a plasmacytoma mice model compared with control mice. Our results show that DHMEQ could potentially be a new type of molecular target agent for multiple myeloma.

³ K. Umezawa, unpublished result from in vivo experiments.

Received 8/ 5/04; revised 3/21/05; accepted 4/29/05.