School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
College of Korean Medicine, Gachon University, Seongnam 13120, Korea.
Molecules. 2019 Mar 1;24(5):878. doi: 10.3390/molecules24050878.
Chronic exposure to cisplatin, a potent anticancer drug, causes irreversible kidney damage. In this study, we investigated the protective effect and mechanism of nine lupane- and ceanothane-type triterpenoids isolated from jujube ( Mill., Rhamnaceae) on cisplatin-induced damage to kidney epithelial LLC-PK1 cells via mitogen-activated protein kinase (MAPK) and apoptosis pathways. Cisplatin-induced LLC-PK1 cell death was most significantly reduced following treatment with 3-dehydroxyceanothetric acid 2-methyl ester (3DC2ME). Additionally, apoptotic cell death was significantly reduced. Expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 was markedly suppressed by 3DC2ME, indicating inhibition of the MAPK pathway. Treatment with 3DC2ME also significantly reduced expression of active caspase-8 and -3, Bcl-2-associated X protein (Bax), and B cell lymphoma 2 (Bcl-2), indicating the inhibition of apoptosis pathways in the kidneys. We also applied the network pharmacological analysis and identified multiple targets of 3DC2ME related to MAPK signaling pathway and apoptosis.
慢性接触顺铂（一种有效的抗癌药物）会导致不可逆转的肾脏损伤。在这项研究中，我们通过丝裂原活化蛋白激酶（MAPK）和细胞凋亡途径，研究了从枣（Rhamnaceae）中分离出的九种羽扇豆烷和环烯醚萜型三萜对顺铂诱导的肾上皮 LLC-PK1 细胞损伤的保护作用及其机制。用 3-去羟基环烯醚萜酸 2-甲酯（3DC2ME）处理后，顺铂诱导的 LLC-PK1 细胞死亡减少最显著。此外，细胞凋亡死亡也显著减少。3DC2ME 显著抑制 c-Jun N-末端激酶（JNK）、细胞外信号调节激酶（ERK）和 p38 的表达，表明 MAPK 途径受到抑制。用 3DC2ME 处理还显著降低了活性半胱天冬酶-8 和 -3、Bcl-2 相关 X 蛋白（Bax）和 B 细胞淋巴瘤 2（Bcl-2）的表达，表明 3DC2ME 抑制了肾脏中的细胞凋亡途径。我们还应用网络药理学分析，确定了 3DC2ME 与 MAPK 信号通路和细胞凋亡相关的多个靶点。
