Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myelorna
Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myelorna
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DOI：
10.1182/blood-2007-01-065888
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发表时间：
2007-11-01
期刊：
影响因子：
20.3
通讯作者：
Orlowski, Robert Z.
中科院分区：
文献类型：
--
作者：
Kuhn, Deborah J.;Chen, Qing;Orlowski, Robert Z.
蛋白酶体已成为癌症治疗的一个重要靶点，硼替佐米是一类可逆的蛋白酶体抑制剂，用于治疗复发性/难治性多发性骨髓瘤（MM）。然而，许多患者的疾病对硼替佐米没有反应，而其他患者则产生耐药性，这表明需要其他具有增强活性的抑制剂。因此，我们评估了一种新的，不可逆的，环氧霉素相关的蛋白酶体抑制剂，卡非佐米。在MM模型中，该药物有效结合并特异性抑制胰凝乳蛋白酶样蛋白酶体和免疫蛋白酶体活性，导致泛素化底物蓄积。卡非佐米诱导剂量和时间依赖性的增殖抑制，最终导致细胞凋亡。程序性细胞死亡与c-Jun-N-末端激酶的激活、线粒体膜去极化、细胞色素c的释放以及内源性和外源性caspase途径的激活相关。该药物还可抑制患者来源的MM细胞和其他血液恶性肿瘤患者的肿瘤细胞的增殖并激活凋亡。重要的是，与硼替佐米相比，卡非佐米显示出更高的疗效，并且对硼替佐米耐药MM细胞系和来自临床硼替佐米耐药患者的样本具有活性。卡非佐米还克服了对其他常规药物的耐药性，并与地塞米松协同作用以增强细胞死亡。总之，这些数据为卡非佐米在MM中的临床评价提供了依据。
The proteasome has emerged as an important target for cancer therapy with the approval of bortezomib, a first-in-class, reversible proteasome inhibitor, for relapsed/refractory multiple myeloma (MM). However, many patients have disease that does not respond to bortezomib, whereas others develop resistance, suggesting the need for other inhibitors with enhanced activity. We therefore evaluated a novel, irreversible, epoxomicin-related proteasome inhibitor, carfilzomib. In models of MM, this agent potently bound and specifically inhibited the chymotrypsin-like proteasome and immunoproteasome activities, resulting in accumulation of ubiquitinated substrates. Carfilzomib induced a dose- and time-dependent inhibition of proliferation, ultimately leading to apoptosis. Programmed cell death was associated with activation of c-Jun-N-terminal kinase, mitochondrial membrane depolarization, release of cytochrome c, and activation of both intrinsic and extrinsic caspase pathways. This agent also inhibited proliferation and activated apoptosis in patient-derived MM cells and neoplastic cells from patients with other hematologic malignancies. Importantly, carfilzomib showed increased efficacy compared with bortezomib and was active against bortezomib-resistant MM cell lines and samples from patients with clinical bortezomib resistance. Carfilzomib also overcame resistance to other conventional agents and acted synergistically with dexamethasone to enhance cell death. Taken together, these data provide a rationale for the clinical evaluation of carfilzomib in MM.