Author:
Jiang Yining,Wang Yunyun,Zhao Liyan,Yang Wenzhuo,Pan Lin,Bai Yang,Wang Yubo,Li Yunqian
Abstract
Abstract
Background
Cyclin-dependent kinase-2 (CDK-2) is an important regulatory factor in the G1/S phase transition. CDK-2 targeting has been shown to suppress the viability of multiple cancers. However, the exploration and application of a CDK-2 inhibitor in the treatment of glioblastoma are sparse.
Methods
We synthesized P129 based on isolongifolanone, a natural product with anti-tumor activity. Network pharmacology analysis was conducted to predict the structural stability, affinity, and pharmacological and toxicological properties of P129. Binding analysis and CETSA verified the ability of P129 to target CDK-2. The effect of P129 on the biological behavior of glioma cells was analyzed by the cell counting kit-8, colony formation, flow cytometry, and other experiments. Western blotting was used to detect the expression changes of proteins involved in the cell cycle, cell apoptosis, and epithelial–mesenchymal transition.
Results
Bioinformatics analysis and CETSA showed that P129 exhibited good intestinal absorption and blood–brain barrier penetrability together with high stability and affinity with CDK-2, with no developmental toxicity. The viability, proliferation, and migration of human glioma cells were significantly inhibited by P129 in a dose- and time-dependent manner. Flow cytometry and western blotting analyses showed G0/G1 arrest and lower CDK-2 expression in cells treated with P129 than in the controls. The apoptotic ratio of glioma cells increased significantly with increasing concentrations of P129 combined with karyopyknosis and karyorrhexis. Apoptosis occurred via the mitochondrial pathway.
Conclusion
The pyrazole ring-containing isolongifolanone derivate P129 exhibited promising anti-glioma activity by targeting CDK-2 and promoting apoptosis, indicating its potential importance as a new chemotherapeutic option for glioma.
Funder
Natural Science Foundation of Jiangsu Province
Jilin Province Science and Technology Development Planning Project
Health and Wellness Technology Enhancement Project of Jilin Province
the S&T Development Planning Program of Jilin Province
National Nature and Science Foundation of China
Jilin Province Medical and Health Talent Project
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Endocrine and Autonomic Systems,Endocrinology,Oncology,Endocrinology, Diabetes and Metabolism