文章：

Nimbolide靶向BCL2，在临床前华氏巨球蛋白瘤模型中诱导细胞凋亡

Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia

原文发布日期：2014-11-07

DOI: 10.1038/bcj.2014.74

类型: Original Article

开放获取: 是

英文摘要：

Neem leaf extract (NLE) has medicinal properties, which have been attributed to its limonoid content. We identified the NLE tetranorterpenoid, nimbolide, as being the key limonoid responsible for the cytotoxicity of NLE in various preclinical models of human B-lymphocyte cancer. Of the models tested, Waldenströms macroglobulinemia (WM) cells were most sensitive to nimbolide, undergoing significant mitochondrial mediated apoptosis. Notably, nimbolide toxicity was also observed in drug-resistant (bortezomib or ibrutinib) WM cells. To identify putative targets of nimbolide, relevant in WM, we used chemoinformatics-based approaches comprised of virtual in silico screening, molecular modeling and target–ligand reverse docking. In silico analysis revealed the antiapoptotic protein BCL2 was the preferential binding partner of nimbolide. The significance of this finding was further tested in vitro in RS4;11 (BCL2-dependent) tumor cells, in which nimbolide induced significantly more apoptosis compared with BCL2 mutated (Jurkat BCL2Ser70-Ala) cells. Lastly, intraperitoneal administration of nimbolide in WM tumor xenografted mice, significantly reduced tumor growth and IgM secretion in vivo, while modulating the expression of several proteins as seen on immunohistochemistry. Overall, our data demonstrate that nimbolide is highly active in WM cells, as well as other B-cell cancers, and engages BCL2 to exert its cytotoxic activity.

摘要翻译： 

印楝叶提取物（NLE）具有药用特性，这归因于其所含的柠檬苦素类化合物。我们发现NLE中的四去甲三萜类化合物印楝素（nimbolide）是在多种临床前人类B淋巴细胞癌症模型中导致NLE细胞毒性的关键柠檬苦素。在测试的模型中，华氏巨球蛋白血症（WM）细胞对印楝素最为敏感，会经历显著的线粒体介导的凋亡。值得注意的是，在耐药（硼替佐米或伊布替尼）的WM细胞中也观察到了印楝素的毒性作用。为了确定印楝素在WM中的潜在作用靶点，我们采用了基于化学信息学的方法，包括虚拟计算机筛选、分子建模和靶点-配体反向对接。计算机分析显示，抗凋亡蛋白BCL2是印楝素的优先结合伴侣。这一发现的意义在体外实验中进一步验证：在RS4;11（BCL2依赖性）肿瘤细胞中，印楝素诱导的凋亡显著多于BCL2突变（Jurkat BCL2Ser70-Ala）细胞。最后，在WM肿瘤异种移植小鼠中腹腔注射印楝素，显著降低了体内肿瘤生长和IgM分泌，同时通过免疫组织化学检测发现调节了多种蛋白的表达。总体而言，我们的数据表明，印楝素在WM细胞及其他B细胞癌症中具有高度活性，并通过作用于BCL2来发挥其细胞毒性活性。

原文链接：

Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenströms macroglobulinemia