The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo
The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo
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DOI：
10.1182/blood-2008-09-175430
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发表时间：
2009-05-07
期刊：
影响因子：
20.3
通讯作者：
Grever, Michael R.
中科院分区：
文献类型：
--
作者：
Lucas, David M.;Edwards, Ryan B.;Grever, Michael R.
晚期B细胞急性淋巴细胞性白血病(ALL)和慢性淋巴细胞性白血病(CLL)的治疗选择有限。现有的治疗方法还会耗尽T淋巴细胞，使患者面临威胁生命的感染风险。在国家癌症研究所的细胞系筛查中，结构独特的天然产品西尔维斯特产生了一种不同寻常的细胞毒性模式，这表明它在白血病中具有活性和对B细胞的选择性。我们使用原代人类B-白血病细胞，建立了B-白血病细胞系，并建立了动物模型，研究了西尔维斯特的疗效。在CLL细胞中，西维斯特罗LC(50)(致死浓度为50%)在72小时为6.9 nM。在此浓度下，有或无del(17p13.1)异常患者的细胞敏感性没有差异。在分离的细胞和全血中，西维司酮对B细胞的细胞毒作用强于T细胞。由于翻译抑制和随后的线粒体损伤，西维斯特罗导致Mcl-1表达的早期减少，这是通过产生活性氧和膜去极化来证明的。在体内，西尔维斯特可显著减少E-MU-TCL-1转基因小鼠的B细胞，显著延长697只异种移植的严重联合免疫缺陷(SCID)小鼠的存活时间，且无明显毒性。这些数据表明，西维斯特在体外和体内对B细胞都有疗效，并确定翻译抑制是B细胞白血病的潜在治疗靶点。(血。2009；113：4656-4666)
Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited. Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections. In the National Cancer Institute cell line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B cells. We investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models. In CLL cells, silvestrol LC(50) (concentration lethal to 50%) is 6.9 nM at 72 hours. At this concentration, there is no difference in sensitivity of cells from patients with or without the del( 17p13.1) abnormality. In isolated cells and whole blood, silvestrol is more cytotoxic toward B cells than T cells. Silvestrol causes early reduction in Mcl-1 expression due to translational inhibition with subsequent mitochondrial damage, as evidenced by reactive oxygen species generation and membrane depolarization. In vivo, silvestrol causes significant B-cell reduction in E mu-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (SCID) mice without discernible toxicity. These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias. (Blood. 2009;113:4656-4666)