Hou Yi, Pi Chao, Feng Xianhu, Wang Yuanyuan, Fu Shaozhi, Zhang Xiaomei, Zhao Ling, Wei Yumeng
Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, No. 3-5, Zhongshan Road, Jiangyang District, Luzhou, Sichuan 646000, P.R. China.
Department of Oncology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, Sichuan 646000, P.R. China.
Mol Ther Oncolytics. 2020 Sep 1;19:67-78. doi: 10.1016/j.omto.2020.08.018. eCollection 2020 Dec 16.
In this study, a pair of chiral baicalin (BA) derivatives were synthesized by combining BA with phenylalanine methyl ester based on molecular docking technology, namely BAD and BAL. Cell cytotoxicity trails showed that the cell growth inhibitory effects of both BAD and BAL were increased by 8- to 12-fold compared with BA on A549 cells. Flow cytometry showed that the apoptotic rates of 50 μg/mL BA, BAD, and BAL to A549 cells for 48 h were 17.94%, 24.32%, and 39.69%, respectively. Western blotting analysis showed that BAD and BAL could promote Bax, caspase-3, and caspase-9 expression and inhibit Bcl-2 expression by inhibiting the expression of p-Akt. The tumor inhibition rates of BA, BAD, and BAL in nude mice of tumor-bearing experiment lasting for 24 days were 35.01%, 53.30%, and 59.35%, respectively. These results and showed that BAL had higher antitumor activity than did BAD and BA, which were related to promotion of the apoptosis of tumor cells by inhibiting the expression of p-Akt on PI3K/Akt pathway. This study provides an experimental basis for the development of a new configuration of BA for the treatment of cancer.
在本研究中，基于分子对接技术，通过将黄芩苷（BA）与苯丙氨酸甲酯结合，合成了一对手性黄芩苷衍生物，即BAD和BAL。细胞毒性实验表明，与BA相比，BAD和BAL对A549细胞的生长抑制作用提高了8至12倍。流式细胞术显示，50μg/mL的BA、BAD和BAL作用于A549细胞48小时后的凋亡率分别为17.94%、24.32%和39.69%。蛋白质免疫印迹分析表明，BAD和BAL可通过抑制p-Akt的表达来促进Bax、caspase-3和caspase-9的表达，并抑制Bcl-2的表达。在持续24天的荷瘤裸鼠实验中，BA、BAD和BAL的肿瘤抑制率分别为35.01%、53.30%和59.35%。这些结果表明，BAL比BAD和BA具有更高的抗肿瘤活性，这与通过抑制PI3K/Akt途径上p-Akt的表达来促进肿瘤细胞凋亡有关。本研究为开发用于治疗癌症的新型构型黄芩苷提供了实验依据。
