Identifying the Effect of Celastrol Against Ovarian Cancer With Network Pharmacology and In Vitro Experiments

Abstract

Aim: We aimed to reveal the function of celastrol in the treatment of ovarian cancer using network pharmacology and molecular docking. Background: Ovarian cancer is a growth of cells that forms in the ovaries. Celastrol is a useful bioactive compound derived from the root of the thunder god vine. Method: Celastrol and ovarian cancer targets were determined by analyzing datasets. Protein-protein interaction (PPI) networks were obtained with network pharmacology. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. Molecular docking using SWISS-MODEL, CB-Dock and Discovery Studio was conducted. A methylthiazolyltetrazolium bromide (MTT) assay was performed to evaluate cell proliferation. Cell apoptosis and cell cycle were measured with a fluorescence assay. Reverse transcription PCR (RT-PCR) and Western blot were performed to measure the expression of core targets. Result: Celastrol possessed 29 potential targets, while ovarian cancer possessed 471 potential targets. The core PPI network contained 163 nodes and 4,483 edges. The biological processes identified in the GO analysis indicated that the targets were related with the cellular response to DNA damage stimulus, DNA recombination, and cell proliferation, among other processes. The KEGG analysis indicated that the pathways were related with the cell cycle, viral carcinogenesis, and MAPK signaling pathway, among others. The three core targets shared between the core PPI network and celastrol targets were MYC, CDC37, and FN1. Celastrol directly combined with the targets according to the results from CB-Dock and Discovery Studio. Celastrol inhibited ovarian cancer cell proliferation and promoted ovarian cancer cell apoptosis in a dose-dependent manner. RT-PCR and Western blot analyses showed that celastrol inhibited core target expression. In addition, celastrol also influenced the related inflammatory signaling pathways in ovarian cancer cells. Conclusion: Celastrol exerts effective antitumor activity toward ovarian cancer. Celastrol regulated cell proliferation, DNA repair and replication, apoptotic processes, and inflammatory responses in ovarian cancer cells.

Keywords: celastrol; inflammatory responses; molecular docking; network pharmacology; ovarian cancer.