Exploring the potential mechanism of artesunate in intervening with U87 cells and U251 cells with distinct therapeutic effects on the basis of transcriptome sequencing and network pharmacology
10.16438/j.0513-4870.2022-0821
- VernacularTitle:基于转录组测序和网络药理学探究青蒿琥酯干预U87和U251脑胶质瘤细胞的药效差异机制
- Author:
Tao LI
1
;
Xia MAO
2
;
Yan-qiong ZHANG
2
;
Na LIN
2
;
Takashi SATO
3
;
Koji MIZUNO
3
;
Katsuki OKUYAMA
3
;
Feng HUANG
1
Author Information
1. School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming 650500, China
2. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
3. Department of Biochemistry, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
- Publication Type:Research Article
- Keywords:
artesunate;
glioma;
transcriptome sequencing;
network pharmacology;
pharmacological mechanism
- From:
Acta Pharmaceutica Sinica
2023;58(6):1475-1483
- CountryChina
- Language:Chinese
-
Abstract:
Artesunate possesses the potential of intervening with glioma, however, its pharmacological mechanisms remain unclarified. Firstly, the effects of artesunate on cell activity, proliferation and apoptosis of U87 and U251 human glioma cells were explored. It was found that artesunate exerted stronger inhibitory effects on the activity and proliferation of U87 cells than U251 cells. It could significantly promote apoptosis in U87 cells (P < 0.05), while only high dose of artesunate can promote that of U251 cells (P < 0.01), detected by Hoechst and TUNEL cell apoptosis staining. Further, the differential expression gene sets between artesunate-sensitive and non-sensitive cell line, as well the therapeutic effects-related genes of artesunate were obtained through transcriptome sequencing and differential data analysis by using the lysates of U87 and U251 cells before and after artesunate treatment, aiming to explore the molecular mechanism of distinct artesunate sensitivity to two types of cells. Then, key putative targets that related to therapeutic effects were screened by constructing the interaction network of differential genes of three above comparison groups, and calculating their topological characteristics. Pathway enrichment analysis showed that those key putative targets were significantly enriched in several signaling pathways that were closely associated with the main pathological changes of glioma, among which apoptosis-related activating transcription factor 4 (ATF4)-DNA damage induced transcript 3 (DDIT3)- polyadenosine diphosphate ribose polymerase 1 (PARP1) signaling axis was the most enriched in. Molecular docking indicated that artesunate had fine binding affinities with ATF4 and DDIT3. Above all, this study preliminarily revealed that ATF4-DDIT3-PARP1 signaling axis is the target pathway of artesunate intervening with U87 glioma cells, and PARP1 may be an important gene for U251 cells to develop resistance to artesunate. Our results not only provide fundamental experimental evidence for artesunate as a potential therapeutic drug in glioma treatment, but shed light into overcoming drug resistance in its clinical therapy.
