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Objectives   Bellidifolin (BEL) is one type of tetraoxygenated xanthone that is particularly found in  Swertia  and  Gentiana  (Gentianaceae). Despite its broad range of pharmacological activities, it is still unclear whether BEL could be used for lung cancer treatment. Hence, we presently demonstrate the roles of BEL towards the proliferative inhibition of the prototypical A549 lung cancer cells.Materials and Methods   The antiproliferative activity of BEL was initially verified by cellular experiments. A network pharmacology method was then pursued to assess BEL potential molecular targets from the platform for pharmacological analysis of Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Disease enrichment of potential targets and construction of compound-target-disease network maps were performed based on a total of 20 diseases. Two core targets related to the BEL-mediated effect in A549 cells were obtained by importing potential targets into a protein-protein interaction database (STRING) and also analyzing respective data of related targets into this database. Last, these core targets were examined by in vitro analysis and molecular docking.Results   CCK8 assays indicated that treatment with 50–100  μ m BEL had an inhibitory effect on the proliferation of human A549 lung cancer cells, whereas this effect was time- and concentration-dependent. As control, treatment with 50–100  μ m BEL did not inhibit the proliferation of normal lung epithelial cells (BEAS-2b cell line). H&E staining of BEL-treated A549 cells showed that, upon an increase of drug concentration, nuclear condensation and fragmentation were largely observed. Cell cycle analysis showed that in vitro treatment with 75–100  μ m BEL could block A549 cells in S and G2 phases. Western blot analyses showed that after 72 hours of BEL treatment, the level of caspase-8/3 in A549 cells increased, and the level of PARP1 decreased in a dose-dependent manner. Network pharmacology analysis also indicated that lung cancer was the major disease susceptible to BEL treatment. At the same time, STAT3 and COX-2 were identified as two core targets of BEL in lung cancer treatment. Functional analyses further revealed that the cytotoxicity effect of BEL in A549 cells potentially involved the STAT3/COX-2 pathway. Moreover, molecular docking analysis indicated that BEL structure properly matches with COX-2 and STAT3 in space shape, thus illustrating the putative molecular mechanism of BEL's anticancer effect.Conclusions   Based on a series of in vitro analyses, network pharmacology, and molecular docking, the potential mechanism involving the antiproliferative and cytotoxic effects of BEL in lung cancer cells was investigated. Our study may help providing some theoretical basis for the discovery of novel phytotherapy drugs applicable for the treatment of lung cancer.

Bellidifolin Inhibits Proliferation of A549 Cells by Regulating STAT3/COX-2 Expression and Protein Activity