Ziziphus jujuba var. inermis Rehder is an edible fruit-producing species of the Rhamnaceae family. In the present study, we isolated eight triterpenoids (1–8) from the fruits of Z. jujuba var. inermis and evaluated their apoptotic cell-death-inducing activities in human cancer cell lines (A549, PC-3, and MDA-MB-231). The structures of compounds 1–8 were determined by spectroscopic methods. Among these, four isomers of coumaroyl alphitolic acid showed potent cytotoxic activities on these cancer cells: 3-O-cis-p-coumaroyl alphitolic acid (3), 3-O-trans-p-coumaroyl alphitolic acid (4), 2-O-trans-p-coumaroyl alphitolic acid (5), and 2-O-cis-p-coumaroyl alphitolic acid (6). Moreover, compounds 3–6 induced apoptotic cell death in a concentration-dependent manner. We further investigated the apoptosis-inducing effects of compound 4 in PC-3 cells which triggered the cleavage of procaspase-3, procaspase-7, procaspase-8, bid, and PARP. Compound 4 increased both the mitochondrial reactive oxygen species (ROS) production and the phosphorylation of p38 MAPK (mitogen-activated protein kinase), but decreased the mitochondrial membrane potential. Pretreatment with Mito-TEMPO (a specific mitochondrial-targeted antioxidant) or a specific p38 inhibitor (SB203580) attenuated apoptotic cell death triggered by compound 4 which suggests that compound 4 may induce apoptotic cell death in these cancer cells by increasing the mitochondrial ROS production as well as the subsequent p38 MAPK activation. The study findings provide a rational base to use Ziziphus extracts for cancer treatments in traditional oriental medicine.

中文翻译：

---

枣的 三萜类化合物通过线粒体活性氧的产生诱导人类癌细胞的凋亡†

金丝小枣变种。Inermis Rehder是鼠李科的一种可食用的水果生产物种。在本研究中，我们从酸枣（Z. jujuba var ）的果实中分离了八种三萜（1–8）。麦和评估在人癌细胞系（A549，PC-3和MDA-MB-231）他们的凋亡性细胞死亡诱导活性。化合物1–8的结构通过光谱方法确定。其中，香豆酰基壬二酸的四个异构体显示出对这些癌细胞有效的细胞毒性活性：3 -O-顺-对-香豆酰基壬二酸（3），3 -O-反式-对-香豆酰基壬二酸（4），2-O-反式-对-香豆酰基壬二酸（5）和2 -O-顺式-对-香豆酰基壬二酸（6）。此外，化合物3–6以浓度依赖性方式诱导凋亡细胞死亡。我们进一步研究了化合物4在PC-3细胞中的凋亡诱导作用，该作用触发了procaspase-3，procaspase-7，procaspase-8，bid和PARP的裂解。化合物4增加了线粒体活性氧（ROS）的产生和p38 MAPK（有丝分裂原激活的蛋白激酶）的磷酸化，但降低了线粒体膜电位。用Mito-TEMPO（一种针对特定线粒体的抗氧化剂）或一种特定的p38抑制剂（SB203580）进行的预处理可减轻化合物4触发的凋亡细胞死亡，这表明化合物4可通过增加线粒体ROS的产生来诱导这些癌细胞的凋亡性细胞死亡。以及随后的p38 MAPK激活。该研究结果为在传统的东方医学中使用吉普车提取物进行癌症治疗提供了合理的依据。