Hu Xiaopeng, Chen Tie, Zhang Shuquan, Zhang Qian, Li Chenyang, Wang Xiaodong
School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China.
Department of Biochemistry, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Malaysia.
Basic Clin Pharmacol Toxicol. 2022 Jan;130(1):56-69. doi: 10.1111/bcpt.13673. Epub 2021 Oct 29.
Oleandrigenin-3-O-β-D-diginoside (a derivative of odoroside A), isolated and purified by our group, has seldom been explored for its pharmacological activity. This study aimed at clarifying the mechanisms towards the leukaemia-suppressive role of odoroside A (compound #1) and its derivative, oleandrigenin-3-O-β-D-diginoside (compound #2) isolated from Nerium oleander. Viability and nuclear morphology change were assessed by CCK-8 assay and fluorescence microscope, respectively. Then, the cell apoptosis and autophagy induced by the compounds were detected by flow cytometry and Western blot. Xenograft model of nude mice was also applied to measure the leukaemia-suppressive effects of compound #2 in vivo. The result displayed that compound #1 and compound #2 inhibited the proliferation of HL60 and K562 cells and stronger effects were found in HL60 than K562 cells. Both of the compounds induced a dose-dependent apoptosis and autophagy in HL60 cells, where compound #2 was more potent than compound #1. Compound #2 also demonstrated a time-dependent apoptosis and autophagy in HL60 cells. Furthermore, ROS generation and JNK phosphorylation occurred in a dose-dependent manner in the cells treated with compound #2. Mitochondria also played critical role, proved by the decrease of Bcl-2, the release of cyto c to cytosol and the activation of caspase-3 and caspase-9. Moreover, the antitumour effects of compound #2 were validated in the nude mouse xenograft model in vivo. Odoroside A and its derivative inhibited the growth of leukaemia by inducing apoptosis and autophagy through the activation of ROS/JNK pathway. These results suggest that the compounds can serve as potential antitumour agents against leukaemia, especially acute myeloid leukaemia (AML).
我们团队分离纯化得到的夹竹桃次苷元 -3-O-β-D-洋地黄糖苷（odoroside A的衍生物），其药理活性鲜少被研究。本研究旨在阐明从夹竹桃中分离得到的odoroside A（化合物#1）及其衍生物夹竹桃次苷元 -3-O-β-D-洋地黄糖苷（化合物#2）对白血病的抑制作用机制。分别通过CCK-8法和荧光显微镜评估细胞活力和细胞核形态变化。然后，通过流式细胞术和蛋白质免疫印迹法检测化合物诱导的细胞凋亡和自噬。还应用裸鼠异种移植模型在体内检测化合物#2的白血病抑制作用。结果显示，化合物#1和化合物#2抑制HL60和K562细胞的增殖，且在HL60细胞中的作用强于K562细胞。两种化合物均在HL60细胞中诱导剂量依赖性的凋亡和自噬，其中化合物#2比化合物#1更有效。化合物#2在HL60细胞中也表现出时间依赖性的凋亡和自噬。此外，在用化合物#2处理的细胞中，活性氧生成和JNK磷酸化呈剂量依赖性发生。线粒体也发挥了关键作用，这通过Bcl-2的减少、细胞色素c释放到细胞质以及caspase-3和caspase-9的激活得以证明。此外，化合物#2的抗肿瘤作用在体内裸鼠异种移植模型中得到验证。Odoroside A及其衍生物通过激活ROS/JNK途径诱导凋亡和自噬来抑制白血病的生长。这些结果表明，这些化合物可作为潜在的抗白血病抗肿瘤药物，尤其是针对急性髓系白血病（AML）。
