Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma.
Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma.
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DOI：
10.3109/10428194.2012.728597
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发表时间：
2013-04
影响因子：
2.6
通讯作者：
Stewart AK
中科院分区：
文献类型：
--
作者：
Zhu YX;Kortuem KM;Stewart AK
虽然已经提出了几种机制来解释沙利度胺，来那度胺和泊马度胺在多发性骨髓瘤（MM）中的活性，包括可证实的抗血管生成，抗增殖和免疫调节作用，但精确的细胞靶点和分子机制最近才变得清晰。一项具有里程碑意义的研究最近确定cereblon（CRBN）作为沙利度胺致畸性的主要靶点。随后证明，CRBN也是沙利度胺和相关药物（所谓的免疫调节药物（IMiD））的抗骨髓瘤活性所需的。发现CRBN低表达与MM细胞系和原代MM细胞中的耐药性相关。鉴定的CRBN的下游靶标之一是干扰素调节因子4（IRF 4），其对于骨髓瘤细胞存活至关重要并且通过IMiD治疗下调。CRBN还涉及IMiD的几种作用，如肿瘤坏死因子-α（TNF-α）和T细胞免疫调节活性的下调，表明IMiD的多效性作用是通过与CRBN结合而启动的。未来对CRBN下游信号传导的研究将有助于阐明IMiD作用的潜在机制，并最终导致开发具有更特异性抗骨髓瘤活性的新药。它还可以提供预测IMiD应答和耐药性的生物标志物。
Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance.
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影响因子：
--
作者：
Braga WM;Atanackovic D;Colleoni GW
通讯作者：
Colleoni GW
影响因子：
4.8
作者：
Bjorklund, Chad C.;Ma, Wencai;Orlowski, Robert Z.
通讯作者：
Orlowski, Robert Z.
影响因子：
9.9
作者：
Higgins, JJ;Pucilowska, J;Rooney, JP
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Rooney, JP
影响因子：
56.9
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
通讯作者：
Handa, Hiroshi
影响因子：
4.8
作者：
Keifer, JA;Guttridge, DC;Baldwin, AS
通讯作者：
Baldwin, AS