A Network Pharmacology Guided Mechanism of Action Study on Oldenlandia diffusa Against Osteosarcoma

Abstract

Background: Osteosarcoma (OS) is the most prevalent primary bone sarcoma in the global child and young adult population, and the current mainstream treatment regimens are not very effective. The unique efficacy of traditional Chinese medicine (TCM) for cancers has recently received increasing attention. Oldenlandia diffusa (OD) is commonly used as adjuvant therapy for various cancers in Chinese herb medicine (CHM) with its unique pharmacological activities, but its therapeutic effect as well as the underlying mechanism against OS has yet to be systematically investigated. Objective: This study aims to find the underlying active mechanism of OD against OS. Methods: The candidate ingredients as well as drug targets of OD were obtained from the Traditional Chinese Medicine System Pharmacology (TCMSP) database, respectively. Meanwhile, the OS diseaserelated targets were acquired from GeneCards and MalaCards online databases. Then, by using Venny 2.1, the common key targets were imported into the STRING database to acquire their interaction relationship, and imported this PPI network file (.csv) into Cytoscape 3.6.0 software and merged to obtain PPI network intersections. Meanwhile, the MCODE plugin of Cytoscape was also used to further trim the core therapeutic targets. GO and KEGG enrichment and molecular docking analyses were performed to predict the underlying mechanism of OD against OS. Furthermore, in silico analysis results were validated by a series of cellular functional and molecular biological assays. Results: A total of 131 putative targets were identified to be involved in the anti-OS activity of OD. The PPI network, GO as well as KEGG analyses revealed that the 18 core targets were closely related to cell proliferation, apoptosis. Importantly, the subsequent in vitro assays verified that the suppressive effect of OD on OS cell growth indeed resulted from disrupted apoptosis and cell proliferation via Akt and ERK signaling pathways. Furthermore, our results showed that quercetin, beta-sitosterol and 2-methoxy-3- methyl-9,10-anthraquinone were the key ingredients, while PTGS2, CASP3 and JUN were the key targets in delivering the pharmacological activities of OD against OS, thus providing an insight into the anti-OS action of OD from a holistic perspective. Conclusion: In summary, our results indicate that OD has good prospects in the treatment of OS.