布鲁顿酪氨酸激酶抑制剂伊布替尼对骨髓瘤细胞具有细胞毒性，并通过 NF-κB 显著增强硼替佐米和来那度胺的活性。

BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB.

机构信息

School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.

出版信息

Cell Signal. 2013 Jan;25(1):106-12. doi: 10.1016/j.cellsig.2012.09.008. Epub 2012 Sep 11.

DOI:10.1016/j.cellsig.2012.09.008

Abstract

Ibrutinib (previously known as PCI-32765) has recently shown encouraging clinical activity in chronic lymphocytic leukaemia (CLL) effecting cell death through inhibition of Bruton's tyrosine kinase (BTK). In this study we report for the first time that ibrutinib is cytotoxic to malignant plasma cells from patients with multiple myeloma (MM) and furthermore that treatment with ibrutinib significantly augments the cytotoxic activity of bortezomib and lenalidomide chemotherapies. We describe that the cytotoxicity of ibrutinib in MM is mediated via an inhibitory effect on the nuclear factor-κB (NF-κB) pathway. Specifically, ibrutinib blocks the phosphorylation of serine-536 of the p65 subunit of NF-κB, preventing its nuclear translocation, resulting in down-regulation of anti-apoptotic proteins Bcl-xL, FLIP(L) and survivin and culminating in caspase-mediated apoptosis within the malignant plasma cells. Taken together these data provide a platform for clinical trials of ibrutinib in myeloma and a rationale for its use in combination therapy, particularly with bortezomib.

摘要

伊布替尼（以前称为 PCI-32765）最近在慢性淋巴细胞白血病（CLL）中显示出令人鼓舞的临床活性，通过抑制布鲁顿酪氨酸激酶（BTK）来实现细胞死亡。在这项研究中，我们首次报告伊布替尼对多发性骨髓瘤（MM）患者的恶性浆细胞具有细胞毒性，并且用伊布替尼治疗可显著增强硼替佐米和来那度胺化疗的细胞毒性作用。我们描述了伊布替尼在 MM 中的细胞毒性是通过对核因子-κB（NF-κB）途径的抑制作用介导的。具体来说，伊布替尼阻止 NF-κB p65 亚基丝氨酸-536 的磷酸化，防止其核易位，导致抗凋亡蛋白 Bcl-xL、FLIP（L）和存活素下调，并最终导致恶性浆细胞中的 caspase 介导的细胞凋亡。这些数据共同为伊布替尼在骨髓瘤中的临床试验提供了一个平台，并为其联合治疗，特别是与硼替佐米联合治疗提供了理论依据。