Polyphyllin D induces apoptosis in human erythrocytes through Ca2+ rise and membrane permeabilization
Polyphyllin D induces apoptosis in human erythrocytes through Ca2+ rise and membrane permeabilization
复制标题
DOI：
10.1007/s00204-012-0808-4
复制
发表时间：
2012-05-01
影响因子：
6.1
通讯作者：
Kong, S. K.
中科院分区：
文献类型：
--
作者：
Gao, Minghui;Cheung, K. L.;Kong, S. K.
多叶连翘苷D（Polyphyllin D，PD）是从传统草药巴黎中分离得到的一种有效的抗癌药物，在我国已被用于治疗癌症多年。PD不是P-糖蛋白的底物，它可以绕过癌细胞系R-HepG 2的多药耐药。然而，PD对人红细胞中细胞死亡诱导的影响仍然未知。鉴于PD是一种小分子，可以降低线粒体膜电位并在分离的线粒体中释放凋亡诱导因子（AIF），我们假设PD在缺乏线粒体的人红细胞中的致凋亡作用将是最小的。因此，本研究试图评估PD对人红细胞溶血和凋亡的体外作用。通过流式细胞术和共聚焦显微镜测定PD治疗后人红细胞（RBC）中的细胞凋亡（也称为红细胞凋亡或红细胞凋亡），以确定磷脂酰丝氨酸外化和其他细胞凋亡特征事件。与我们的预测相反，PD引起人RBC中的溶血和红细胞增多/红细胞凋亡。从机制上讲，胞质Ca 2+离子水平的升高似乎是PD介导的红细胞凋亡/红细胞凋亡中的关键但不是唯一的介质，因为外部Ca 2+的耗尽不能消除PD效应。此外，PD能够以类似于毛地黄皂苷的方式渗透RBC血影的膜。总之，我们在这里首次报告了PD在人RBC中的毒性以及其溶血和红细胞凋亡/红细胞凋亡的潜在机制。
Polyphyllin D (PD) is a potent anticancer agent isolated from a traditional medicinal herb Paris polyphylla that has been used in China for many years to treat cancer. PD is not a substrate of p-glycoprotein, and it can bypass the multi-drug resistance in cancer cell line R-HepG2. However, the effect of PD on the induction of cell death in human erythrocytes remains unknown. Given that PD is a small molecule that can depolarize the mitochondrial membrane potential and release apoptosis-inducing factor (AIF) in isolated mitochondria, we hypothesized that the apoptogenic effect of PD in human erythrocytes devoid of mitochondria would be minimal. This study therefore tried to evaluate the in vitro effect of PD on hemolysis and apoptosis in human erythrocytes. Apoptosis in human red blood cells (RBCs), also known as eryptosis or erythroptosis, after PD treatment was determined by flow cytometry and confocal microscopy for the phosphatidyl-serine externalization and other apoptosis feature events. False to our prediction, PD caused hemolysis and eryptosis/erythroptosis in human RBCs. Mechanistically, elevation in the cytosolic Ca2+ ion level seems to be a key but not the only mediator in the PD-mediated eryptosis/erythroptosis because depletion of the external Ca2+ could not eliminate the PD effect. Also, PD was able to permeabilize the membrane of RBC ghosts in a way similar to digitonin. Taken together, we report here for the first time the toxicity of PD in human RBCs as well as its underlying mechanism for the hemolysis and eryptosis/erythroptosis.