Abstract
Marsdeniae tenacissimae Caulis is a traditional Chinese medicine, named Tongguanteng (TGT), that is often used for the adjuvant treatment of cancer. In our previous study, we reported that an ethyl acetate extract of TGT had inhibitory effects against adenocarcinoma A549 cells growth. To identify the components of TGT with anti-tumor activity and to elucidate their underlying mechanisms of action, we developed a technique for isolating compounds, which was then followed by cytotoxicity screening, network pharmacology analysis, and cellular and molecular experiments. We isolated a total of 19 compounds from a TGT ethyl acetate extract. Two novel steroidal saponins were assessed using an ultra-performance liquid chromatography-photodiode array coupled with quadrupole time-of-flight mass (UPLC-ESI-Q/TOF-MS). Then, we screened these constituents for anti-cancer activity against non-small cell lung cancer (NSCLC) in vitro and obtained six target compounds. Furthermore, a compound-target-pathway network of these six bioactive ingredients was constructed to elucidate the potential pathways that controlled anticancer effects. Approximately 205 putative targets that were associated with TGT, as well as 270 putative targets that were related to NSCLC, were obtained from online databases and target prediction software. Protein–protein interaction networks for drugs as well as disease putative targets were generated, and 18 candidate targets were detected based on topological features. In addition, pathway enrichment analysis was performed to identify related pathways, including PI3K/AKT, VEGF, and EGFR tyrosine kinase inhibitor resistance, which are all related to metabolic processes and intrinsic apoptotic pathways involving reactive oxygen species (ROS). Then, various cellular experiments were conducted to validate drug-target mechanisms that had been predicted using network pharmacology analysis. The experimental results showed the four C21 steroidal saponins could upregulate Bax and downregulate Bcl-2 expression, thereby changing the mitochondrial membrane potential, producing ROS, and releasing cytochrome C, which finally activated caspase-3, caspase-9, and caspase-8, all of which induced apoptosis in A549 cells. In addition, these components also downregulated the expression of MMP-2 and MMP-9 proteins, further weakening their degradation of extracellular matrix components and type IV collagen, and inhibiting the migration and invasion of A549 cells. Our study elucidated the chemical composition and underlying anti-tumor mechanism of TGT, which may be utilized in the treatment of lung cancer.
Highlights
Lung cancer severely affects human health and survival and has become the main cause of cancer-related deaths over the past several years (Gu et al, 2018)
We reported the isolation of 19 compounds from the dry cane of Marsdeniae tenacissimae Caulis
Compared with the control group (68.40 ± 2.09), the TGT-7 (28 μm), TGT-9 (44 μm), and TGT-13 (29 μm) groups were statistically significant (Figure 9C). These results showed that TGT-7, TGT-9, TGT-13, and TGT-15 could inhibit A549 cells migration and invasion
Summary
Lung cancer severely affects human health and survival and has become the main cause of cancer-related deaths over the past several years (Gu et al, 2018). Extensive evidence indicates that C21 steroid glycosides, extracted by ethyl acetate from TGT, have a significant inhibitory effect against different cancer cell lines, such as A549, Caco-2, SACC83, PC-3, K562, and HepG2 (Ye et al, 2014; Wang et al, 2015). We found that the four C21 steroidal glycosides isolated from TGT had a higher rate of inhibition of A549 cells proliferation than other cell lines (Xu, 2018; Hu et al, 2020). To elucidate the relationship between the chemical structure and cytotoxic activities of steroidal glycosides and to investigate the anti-cancer mechanism of TGT, we isolated and characterized novel compounds from this medicinal plant
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