Abstract
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 μm 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 μm 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 μm 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.
Highlights
Lung cancer is one of the most common malignancies with high mortality worldwide [1]
To evaluate the effect of BEL treatment on the growth/proliferation of lung cancer cells in vitro, A549 cells were treated with increasing doses of BEL concentration at different times. e inhibitory effect of BEL towards the growth of A549 cells increased significantly over time
At 72 hours of BEL treatment, growth inhibition was more evident at 50–100 μm BEL. e one-way ANOVA test showed a significant difference when comparing these results with those obtained from cells treated with 25 μm BEL (P < 0.01). us, a 72 hour timepoint was selected to examine the inhibitory effect of BEL in lung cancer cells (Figure 1). ese data indicate that BEL has a potent antiproliferative activity in human lung cancer cells
Summary
Lung cancer is one of the most common malignancies with high mortality worldwide [1]. The main clinical treatment of lung cancer relates to the use of monoclonal antibodies. This immunotherapy approach frequently leads to side effects, such as allergy, gastrointestinal disorders, and others. Since the large production and purification of monoclonal antibody drugs is expensive and usually time-demanding, searching for novel therapeutic approaches against this aggressive condition is of seminal importance. In this regard, a number of small molecules and peptides have been characterized as potential inhibitors of lung cancer progression. Clinical studies have shown that AL3818 can potentially lead to hypertension-related effects during treatment [4]
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