A novel NF-κB inhibitor DHMEQ selectively targets constitutive NF-κB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo
A novel NF-κB inhibitor DHMEQ selectively targets constitutive NF-κB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo
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DOI：
10.1002/ijc.20688
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发表时间：
2005-03-10
影响因子：
6.4
通讯作者：
Horie, R
中科院分区：
文献类型：
--
作者：
Watanabe, M;Dewan, Z;Horie, R
多发性骨髓瘤（MM）是一种致命的淋巴系统恶性肿瘤，传统的化疗方式无法治愈。核因子κ B（NF-κ B）的强组成性活化是MM细胞的共同特征。在我们的研究中，我们成功地靶向NF-κ B与一种新的NF-κ B抑制剂去羟甲基表氧喹霉素（DHMEQ）。DHMEQ完全消除组成型NF-κ B活性并诱导MM细胞凋亡，而对照外周血单核细胞（PBMC）对DHMEQ处理的NF-κ B抑制和凋亡具有抗性。DHMEQ对NF-κ B的抑制触发半胱天冬酶8和9的激活，以及G 0 G1细胞周期停滞，伴随着抗凋亡基因BclXL和c-FLIP以及细胞周期进展基因细胞周期蛋白D1和D2的下调。DHMEQ介导的MM细胞中血管内皮生长因子（VEGF）产生的抑制提高了DHMEQ消除自分泌VEGF环并增强其的可能性;通过抑制骨髓中的新血管形成来发挥抗肿瘤作用。使用体内NOD/SCID/gammac（null）（NOG）小鼠模型，我们表明DHMEQ对MM细胞的生长具有有效的抑制作用。与具有抑制NF-κ B潜力的其他化合物相比，DHMEQ是一种独特的化合物，其阻断NF-κ B p65易位到细胞核中并选择性靶向肿瘤细胞中活化的NF-κ B。因此，我们的研究提出了一种新的分子靶向治疗在MM。（C）2004年威利-利斯公司。
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.