A novel NF-κB inhibitor DHMEQ selectively targets constitutive NF-κB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo

被引:65
作者
Watanabe, M
Dewan, Z
Okamura, T
Sasaki, M
Itoh, K
Higashihara, M
Mizoguchi, H
Honda, M
Sata, T
Watanabe, T
Yamamoto, N
Umezawa, K
Horie, R
机构
[1] Kitasato Univ, Sch Med, Dept Internal Med 4, Kanagawa 2288555, Japan
[2] Tokyo Med & Dent Univ, Dept Mol Virol, Grad Sch, Tokyo, Japan
[3] Natl Inst Infect Dis, AIDS Res Ctr, Tokyo, Japan
[4] Tokyo Womens Med Univ, Dept Hematol, Tokyo, Japan
[5] Toho Univ, Sch Med, Dept Pathol, Tokyo 153, Japan
[6] Natl Inst Infect Dis, Dept Pathol, Tokyo, Japan
[7] Univ Tokyo, Grad Sch Frontier Sci, Dept Med Genome Sci, Tumor Cell Biol Lab, Tokyo, Japan
[8] Keio Univ, Fac Sci & Technol, Dept Appl Chem, Yokohama, Kanagawa 223, Japan
关键词
myeloma; NF-kappa B; apoptosis; DHMEQ;
D O I
10.1002/ijc.20688
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Multiple myeloma (MM) is a fatal lymphoid malignancy that is incurable with conventional modalities of chemotherapy. Strong and constitutive activation of nuclear factor kappa B (NF-kappaB) is a common characteristic of MM cells. In our study we successfully target NF-kappaB with a novel NF-kappaB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ). DHMEQ completely abrogates constitutive NF-kappaB activity and induces apoptosis of MM cells, whereas control peripheral blood mononuclear cells (PBMC) are resistant to NF-kappaB inhibition and apoptosis by DHMEQ treatment. DHMEQ inhibition of NF-kappaB triggers activation of caspases 8 and 9, as well as G0G1 cell cycle arrest accompanied by downregulation of antiapoptotic genes BclXL and c-FLIP and cell cycle progression gene cyclins D1 and D2. DHMEQ-mediated inhibition of vascular endothelial growth factor (VEGF) production in MM cells raises the possibility that DHMEQ abrogates the autocrine VEGF loop and enhances it; antitumor effects by inhibiting neovascularization in the bone marrow. Using an in vivo NOD/SCID/gammac(null) (NOG) mice model, we show that DHMEQ has a potent inhibitory effect on the growth of MM cells. Compared to other compounds having the potential to inhibit NF-kappaB, DHMEQ is a unique compound that blocks the translocation of NF-KB p65 into the nucleus and selectively targets NF-KB activated in tumor cells. Therefore, our study presents a new molecular target therapy in MM. (C) 2004 Wiley-Liss, Inc.
引用
收藏
页码:32 / 38
页数:7
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