Target Analysis and Mechanism of Podophyllotoxin in the Treatment of Triple-Negative Breast Cancer

Abstract

Background: As the original compound of many podophyllotoxin derivatives, podophyllotoxin has a beneficial antitumor effect. The mechanism of podophyllotoxin activity in triple-negative breast cancer still needs to be explored. Methods: We used cell proliferation assay, scratch and transwell experiments, and cell cycle and apoptosis analyses to observe the intervention effect of podophyllotoxin on breast cancer. Furthermore, we analyzed the differences between GSE31448, GSE65194, and GSE45827 in the Gene Expression Omnibus database (GEO) and explored the differential genes using a STRING database. Centiscape2.2, MCODE cluster analysis and KEGG pathway analysis were used to identify the most significant gene differences. Next, we utilized BATMAN-TCM and TCMSP databases for further screening to identify key genes. Finally, quantitative RT-PCR (qRT-PCR) and Western blotting were performed to detect the expression of key targets. Results: Our research confirmed that podophyllotoxin could not only inhibit the migration and invasion of triple-negative breast cancer but also affect the cell cycle and induce apoptosis. In total, 566 differential genes were obtained by using the GEO database. After topological network analysis, cluster analysis, and molecular docking screening, we finally identified PLK1, CCDC20, and CDK1 as key target genes. The results of the qRT-PCR assay showed that the mRNA levels of PLK1, CDC20, and CDK1 decreased, while the expression of upstream P53 increased, after drug induction. The Gene Set Enrichment Analysis (GSEA) and conetwork analysis showed that PLK1 is a more critical regulatory factor. Further Western blotting analysis revealed that there was a negative regulatory relationship between the key gene PLK1 and P53 on the protein level. The results were presented as the mean ± standard deviation of triplicate experiments and P<0.05 was considered to indicate a statistically significant difference. Conclusion: Podophyllotoxin has an intervention effect on the development of triplenegative breast cancer. The expression of PLK1, CDC20, and CDK1 in the cell cycle

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

“…It led to the production of ROS and γ-H2AX and activated the ATM/p53/p21 pathway to trigger DNA damage response in human breast cancer cells, and also induced mitochondrial apoptosis and cell cycle arrest. Zhang et al (2020) comprehensively analyzed the molecular mechanism of PTOX on TNBC, and they suggested that PLK1 may be a downstream key gene. Furthermore, many drug delivery system (DDS)-based products were developed to improve aqueous solubility and reduce the side effects of PTOX.…”

The mechanism research on the anti‐liver fibrosis of emodin based on network pharmacology

“…For example, the finding reported by Zhang showed that CentiScape and MCODE plug‐ins were used to mine the functional modules associated with the Mycobacterium tuberculosis infection process 37 . The investigation reported by Zhang W identified the Key Genes associated with breast cancer using plug‐in CentiScape and MCODE 16 . Consistent findings were reported by Zhang, indicating that the MCODE plug‐in was utilized to screen hub genes and gene modules in the PPI network, obtaining the potential key genes for colorectal cancer (CRC) liver metastasis 38 .…”

“…The genes at the top of the degree distribution (≥ 95% percentile) in the significantly perturbed networks were defined as central genes 15 . Moreover, cluster analysis was performed by the Cytoscape 3.6.1 software plug‐in molecular complex detection (MCODE), which the best protein module can be selected by the score of the node 16 . Besides, the targets including emodin were imported into the STITCH database (http://stitch.embl.de/,ver.5.0), 17 identifying the essential target gene directly linked to the emodin.…”

Podophyllotoxin Induces ROS-Mediated Apoptosis and Cell Cycle Arrest in Human Colorectal Cancer Cells via p38 MAPK Signaling

“…Whereas the anticancer activity of PT is mainly from the inhibition of DNA topoisomerase II and microtubule assembly ( Sathish et al ., 2018 ), studies are revealing more molecular targets of PT. PT was shown to inhibit the growth of triple-negative breast cancer cells such as MDA-MB-231 ( Zhang et al ., 2020 ). We recently reported that PT inhibited the growth of gefitinib-resistant non-small cell lung cancer cells by targeting c-MET ( Oh et al ., 2021 ).…”