Sanguinarine-dependent induction of apoptosis in primary effusion lymphoma cells
Sanguinarine-dependent induction of apoptosis in primary effusion lymphoma cells
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DOI：
10.1158/0008-5472.can-06-3764
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发表时间：
2007-04-15
期刊：
影响因子：
11.2
通讯作者：
Uddin, Shahab
中科院分区：
文献类型：
--
作者：
Hussain, Azhar R.;Al-Jomah, Naif A.;Uddin, Shahab
原发性渗出性淋巴瘤（PEL）是一种无法治愈的侵袭性B细胞恶性肿瘤，对常规化疗迅速产生耐药性。在努力确定新的方法来阻止PEL细胞的增殖，我们发现，血根碱，从根植物Sanguinaria canadendid中分离的天然化合物，抑制细胞增殖，并诱导细胞凋亡，在几个PEL细胞系的剂量依赖性的方式。我们的数据表明，血根碱处理的PEL细胞的死亡受体5（DR 5）的表达上调，通过产生活性氧（ROS），并导致半胱天冬酶-8的激活和截断投标（tBid）。随后，tBid易位到线粒体引起Bax的构象变化，导致线粒体膜电位的损失和细胞色素c释放到胞质溶胶。血根碱诱导的细胞色素c的释放导致半胱天冬酶-9和半胱天冬酶-3的活化和聚（ADP-核糖）聚合酶（PARP）裂解，导致诱导半胱天冬酶依赖性细胞凋亡。此外，我们表明，预处理的PEL细胞与carbenzoxy-Val-Ala-Asp-fluoromethylketone，一种通用的半胱天冬酶抑制剂，废除半胱天冬酶和PARP激活，并防止血根碱诱导的细胞死亡。此外，用血根碱处理PEL细胞下调凋亡抑制蛋白（UP）的表达。最后，N-乙酰半胱氨酸（一种活性氧抑制剂）可抑制血根碱诱导的活性氧产生、DR 5上调、Bax构象变化、caspase-3激活和IAP下调。两者合计，我们的研究结果表明，血根碱是一种有效的诱导细胞凋亡的PEL细胞通过上调DR 5和提高的可能性，这种代理可能是有价值的开发新的治疗方法治疗的PEL。
Primary effusion lymphoma (PEL) is an incurable, aggressive B-cell malignancy that develops rapid resistance to conventional chemotherapy. In efforts to identify novel approaches to block proliferation of PEL cells, we found that sanguinarine, a natural compound isolated from the root plant Sanguinaria canadendid, inhibits cell proliferation and induces apoptosis in a dose-dependent manner in several PEL cell lines. Our data show that sanguinarine treatment of PEL cells results in up-regulation of death receptor 5 (DR5) expression via generation of reactive oxygen species (ROS) and causes activation of caspase-8 and truncation of Bid (tBid). Subsequently, tBid translocates to the mitochondria causing conformational changes in Bax, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. Sanguinarine-induced release of cytochrome c results in activation of caspase-9 and caspase-3 and poly(ADP-ribose) polymerase (PARP) cleavage, leading to induction of caspase-dependent apoptosis. In addition, we show that pretreatment of PEL cells with carbobenzoxy-Val-Ala-Asp-fluoromethylketone, a universal inhibitor of caspases, abrogates caspase and PARP activation and prevents cell death induced by sanguinarine. Moreover, treatment of PEL cells with sanguinarine down-regulates expression of inhibitor of apoptosis proteins (UP). Finally, N-acetylcysteine, an inhibitor of ROS, inhibits sanguinarine-induced generation of ROS, up-regulation of DR5, Bax conformational changes, activation of caspase-3, and down-regulation of IAPs. Taken together, our findings suggest that sanguinarine is a potent inducer of apoptosis of PEL cells via up-regulation of DR5 and raise the possibility that this agent may be of value in the development of novel therapeutic approaches for the treatment of PEL.