Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma
Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma
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DOI：
10.1073/pnas.0503221102
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发表时间：
2005-06-14
影响因子：
11.1
通讯作者：
Anderson, KC
中科院分区：
文献类型：
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作者：
Hideshima, T;Bradner, JE;Anderson, KC
我们已经证明蛋白酶体抑制剂硼替佐米（以前称为PS-341）在临床前模型和复发难治性多发性骨髓瘤（MM）患者中都能触发显著的抗肿瘤活性。最近的研究表明，未折叠和错误折叠的泛素化蛋白不仅可以被蛋白酶体降解，还可以被依赖于组蛋白去乙酰化酶6 （HDAC6）活性的聚合体降解。因此，我们假设抑制这两种蛋白质分解代谢机制可以诱导MM细胞中泛素化蛋白的积累，随后引起显著的细胞应激和细胞毒性。为了证明这一假设，我们分别使用硼替佐米和tubacin抑制蛋白酶体和HDAC6。由于HDAC6抑制，Tubacin以剂量和时间依赖性的方式特异性地触发α -微管蛋白的乙酰化。72 h诱导MM细胞毒性，IC50为5 ~ 20 μ M，通过caspase依赖性凋亡介导；对正常外周血单核细胞无毒性。Tubacin抑制HDAC6与动力蛋白的相互作用，诱导泛素化蛋白的显著积累。它通过c-Jun nh2末端激酶/caspase激活协同增强硼替佐米诱导的细胞毒性。重要的是，这种组合还可以诱导从MM患者骨髓分离的浆细胞产生显著的细胞毒性。最后，MM细胞与骨髓基质细胞的粘附使其生长并抵抗常规治疗；相比之下，即使在贴壁的MM细胞中，tubacin和硼替佐米的组合也会引发毒性。因此，我们的研究表明，tubacin联合硼替佐米介导显著的抗MM活性，为联合治疗改善MM患者预后的临床评估提供了框架。
We have shown that the proteasome inhibitor bortezomib (formerly known as PS-341) triggers significant antitumor activity in multiple myeloma (MM) in both preclinical models and patients with relapsed refractory disease. Recent studies have shown that unfolded and misfolded ubiquitinated proteins are degraded not only by proteasomes, but also by aggresomes, dependent on histone deacetylase 6 (HDAC6) activity. We therefore hypothesized that inhibition of both mechanisms of protein catabolism could induce accumulation of ubiquitinated proteins followed by significant cell stress and cytotoxicity in MM cells. To prove this hypothesis, we used bortezomib and tubacin to inhibit the proteasome and HDAC6, respectively. Tubacin specifically triggers acetylation of alpha-tubulin as a result of HDAC6 inhibition in a dose- and time-dependent fashion. It induces cytotoxicity in MM cells at 72 h with an IC50 of 5-20 mu M, which is mediated by caspase-dependent apoptosis; no toxicity is observed in normal peripheral blood mononuclear cells. Tubacin inhibits the interaction of HDAC6 with dynein and induces marked accumulation of ubiquitinated proteins. It synergistically augments bortezomib-induced cytotoxicity by c-Jun NH2-terminal kinase/caspase activation. Importantly, this combination also induces significant cytotoxicity in plasma cells isolated from MM patient bone marrow. Finally, adherence of MM cells to bone marrow stromal cells confers growth and resistance to conventional treatments; in contrast, the combination of tubacin and bortezomib triggers toxicity even in adherent MM cells. Our studies therefore demonstrate that tubacin combined with bortezomib mediates significant anti-MM activity, providing the framework for clinical evaluation of combined therapy to improve patient outcome in MM.