Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro
Deguelin inhibits expression of IκBα protein and induces apoptosis of B-CLL cells in vitro
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DOI：
10.1038/sj.leu.2404788
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发表时间：
2007-08-01
期刊：
影响因子：
11.4
通讯作者：
Deforce, D.
中科院分区：
文献类型：
--
作者：
Geeraerts, B.;Vanhoecke, B.;Deforce, D.
我们研究鱼藤素，一种天然存在的类鱼藤素，是否能够抑制核因子κ B（NF-κB）结合蛋白（IκBα）的表达，并在体外诱导B细胞慢性淋巴细胞白血病（B-CLL）细胞凋亡。在大多数B-CLL细胞中鱼藤素诱导细胞死亡，并且发现对B-CLL细胞的毒性比对正常单核细胞或B细胞的毒性更大，表明对恶性细胞的选择性。鱼藤素可降低IκBα蛋白的表达，从而与NFκB通路相互作用。以caspase-9和caspase-3的表达和poly-（ADP）-ribose-polymerase裂解为特征。B-CLL细胞暴露于鱼藤素导致Bcl 2相关蛋白（Bax）构象变化和关键存活蛋白髓样细胞白血病序列1（Mcl-1）下调，这与B-CLL患者对治疗的反应有关。鱼藤素保留其在存在白细胞介素-4（B-CLL中的促存活细胞因子）的情况下以及当与50%人血清一起培养时诱导B-CLL细胞凋亡的能力。这些数据表明鱼藤素能够在促存活信号的存在下诱导B-CLL细胞的凋亡，因此值得进一步研究作为单一药剂或与其他抗癌剂组合的临床应用。
We investigated if deguelin, a naturally occurring rotenoid, was able to inhibit nuclear factor kappa B (NF-κB)-binding protein (IκBα) expression and to induce apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells in vitro. Deguelin-induced cell death in the majority of B-CLL cells and was found to be more toxic toward B-CLL cells than to the normal mononuclear or B-cells, suggesting selectivity towards the malignant cells. Deguelin was found to reduce IκBα protein expression, and thus interacts with the NFκB pathway. The induced apoptosis was characterized by processing of caspase-9 and-3 and poly-(ADP)-ribose-polymerase cleavage. Exposure of B-CLL cells to deguelin resulted in Bcl2-associated protein (Bax) conformational changes and downregulation of the key survival protein myeloid cell leukemia sequence 1 (Mcl-1), which is associated with response to treatment in B-CLL patients. Deguelin retained its ability to induce apoptosis in B-CLL cells in the presence of interleukin-4, a pro-survival cytokine in B-CLL, and when cultured with 50% human serum. These data indicate that deguelin is able to induce apoptosis in B-CLL cells in the presence of pro-survival signals and thus merits further investigation for clinical application either as a single agent or in combination with other anticancer agents.