NF-κB as a therapeutic target in multiple myeloma
NF-κB as a therapeutic target in multiple myeloma
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DOI：
10.1074/jbc.m200360200
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发表时间：
2002-05-10
影响因子：
4.8
通讯作者：
Anderson, KC
中科院分区：
文献类型：
--
作者：
Hideshima, T;Chauhan, D;Anderson, KC
我们已经证明，沙利度胺（塔尔）及其免疫调节衍生物（IMiDs），蛋白酶体抑制剂PS-341，和As 2 O3直接作用于多发性骨髓瘤（MM）细胞和骨髓（BM）环境，以克服耐药性。虽然塔尔/IMiDs、PS-341和As 2 O3抑制核因子（NF）-κ B活化，但它们也具有多种多样的其他作用。因此，在这项研究中，我们特别强调NF-κ B阻断在介导抗AM活性中的作用。为了表征特异性NF-κ B阻断对体外AM细胞生长和存活的影响，我们使用了IkappaB激酶（IKK）抑制剂（PS-1145）。我们的研究表明，PS-1145和PS-341分别通过抑制IkappaB α磷酸化和IkappaB α降解，以剂量和时间依赖性方式阻断AM细胞中TNF α诱导的NF-κ B活化。地塞米松（Dex）上调IkappaB α蛋白，增强PS-1145对NF-κ B激活的阻断作用。此外，PS-1145阻断IL-6对Dex诱导的细胞凋亡的保护作用。TNF α诱导的细胞内粘附分子（ICAM）-1在RPM 18226和MMAS细胞上的表达也被PS-1145抑制。此外，PS-1145抑制由AM细胞粘附触发的BMSC的IL-6分泌和粘附于BMSC的AM细胞的增殖。然而，与PS-341相反，PS-1145仅部分（20-50%）抑制AM细胞增殖，表明NF-κ B阻断不能解释PS-341的所有抗AM活性。然而，重要的是，TNF α在PS-1145存在下诱导AM细胞毒性。这些研究表明，特异性靶向NF-κ B可以克服肿瘤细胞与BMSC结合和BM环境中细胞因子分泌所赋予的生长和存活优势。此外，它们为基于靶向NF-κ B的新型AM疗法的临床评价提供了框架。
We have shown that thalidomide (Thal) and its immunomodulatory derivatives (IMiDs), proteasome inhibitor PS-341, and As2O3 act directly on multiple myeloma (MM) cells and in the bone marrow (BM) milieu to overcome drug resistance. Although Thal/IMiDs, PS-341, and As2O3 inhibit nuclear factor (NF)-kappaB activation, they also have multiple and varied other actions. In this study, we therefore specifically address the role of NF-kappaB blockade in mediating anti-AM activity. To characterize the effect of specific NF-kappaB blockade on AM cell growth and survival in vitro, we used an IkappaB kinase (IKK) inhibitor (PS-1145). Our studies demonstrate that PS-1145 and PS-341 block TNFalpha-induced NF-kappaB activation in a dose- and time-dependent fashion in AM cells through inhibition of IkappaBalpha phosphorylation and degradation of IkappaBalpha, respectively. Dexamethasone (Dex) which up-regulates IkappaBalpha protein, enhances blockade of NF-kappaB activation by PS-1145. Moreover, PS-1145 blocks the protective effect of IL-6 against Dex-induced apotosis. TNFa-induced intracellular adhesion molecule (ICAM)-1 expression on both RPM18226 and MMAS cells is also inhibited by PS-1145. Moreover, PS-1145 inhibits both IL-6 secretion from BMSCs triggered by AM cell adhesion and proliferation of AM cells adherent to BMSCs. However, in contrast to PS-341, PS-1145 only partially (20-50%) inhibits AM cell proliferation, suggesting that NF-kappaB blockade cannot account for all of the anti-AM activity of PS-341. Importantly, however, TNFalpha induces AM cell toxicity in the presence of PS-1145. These studies demonstrate that specific targeting of NF-kappaB can overcome the growth and survival advantage conferred both by tumor cell binding to BMSCs and cytokine secretion in the BM milieu. Furthermore, they provide the framework for clinical evaluation of novel AM therapies based upon targeting NF-kappaB.