Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome
Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome
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DOI：
10.1182/blood-2009-05-223677
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发表时间：
2009-10-15
期刊：
影响因子：
20.3
通讯作者：
Bennett, Mark K.
中科院分区：
文献类型：
--
作者：
Parlati, Francesco;Lee, Susan J.;Bennett, Mark K.
卡非佐米是一种临床开发中的蛋白酶体抑制剂，主要靶向组成型蛋白酶体（c20 S）和免疫蛋白酶体（i20 S）中的胰凝乳蛋白酶样（CT-L）亚基。为了研究用卡非佐米抑制CT-L活性的影响，我们开始定量正常和恶性造血细胞中来自c20 S的CT-L亚基β 5和来自i20 S的LMP 7的水平。我们发现i20 S是造血来源细胞中表达的蛋白酶体的主要形式，包括多发性骨髓瘤（MM）CD 138（+）肿瘤细胞。尽管单独特异性抑制LMP 7或β 5不足以产生抗肿瘤反应，但抑制所有蛋白酶体亚单位对血液肿瘤细胞和外周血单核细胞都具有细胞毒性。然而，β 5和LMP 7的选择性抑制足以在MM、非霍奇金淋巴瘤和白血病细胞中诱导抗肿瘤作用，同时使对非转化细胞的毒性最小化。在MM肿瘤细胞中，单独的CT-L抑制足以诱导促凋亡后遗症，包括蛋白酶体底物蓄积、Noxa和半胱天冬酶3/7诱导以及磷酸化eIF 2 α抑制。这些数据支持血液肿瘤细胞对CT-L抑制具有独特敏感性的假设，并提供了对蛋白酶体抑制剂临床安全性特征和抗肿瘤活性的机制理解。（血。2009;114：3439-3447）
Carfilzomib is a proteasome inhibitor in clinical development that primarily targets the chymotrypsin-like (CT-L) subunits in both the constitutive proteasome (c20S) and the immunoproteasome (i20S). To investigate the impact of inhibiting the CT-L activity with carfilzomib, we set out to quantitate the levels of CT-L subunits beta 5 from the c20S and LMP7 from the i20S in normal and malignant hematopoietic cells. We found that the i20S is a major form of the proteasome expressed in cells of hematopoietic origin, including multiple myeloma (MM) CD138(+) tumor cells. Although specific inhibition of either LMP7 or beta 5 alone was insufficient to produce an antitumor response, inhibition of all proteasome subunits was cytotoxic to both hematologic tumor cells and peripheral blood mononuclear cells. However, selective inhibition of both beta 5 and LMP7 was sufficient to induce an antitumor effect in MM, non-Hodgkin lymphoma, and leukemia cells while minimizing the toxicity toward nontransformed cells. In MM tumor cells, CT-L inhibition alone was sufficient to induce proapoptotic sequelae, including proteasome substrate accumulation, Noxa and caspase 3/7 induction, and phospho-eIF2 alpha suppression. These data support a hypothesis that hematologic tumor cells are uniquely sensitive to CT-L inhibition and provide a mechanistic understanding of the clinical safety profile and antitumor activity of proteasome inhibitors. (Blood. 2009;114:3439-3447)