Abstract
Metabolomics can be used to identify potential markers and discover new targets for future therapeutic interventions. Here, we developed a novel application of the metabonomics method based on gas chromatography-mass spectrometry (GC/MS) analysis and principal component analysis (PCA) for rapidly exploring the anticancer mechanism of physapubenolide (PB), a cytotoxic withanolide isolated from Physalis species. PB inhibited the proliferation of hepatocellular carcinoma cells in vitro and in vivo, accompanied by apoptosis-related biochemical events, including the cleavage of caspase-3/7/9 and PARP. Metabolic profiling analysis revealed that PB disturbed the metabolic pattern and significantly decreased lactate production. This suggests that the suppression of glycolysis plays an important role in the anti-tumour effects induced by PB, which is further supported by the decreased expression of glycolysis-related genes and proteins. Furthermore, the increased level of p53 and decreased expression of p-Akt were observed, and the attenuated glycolysis and enhanced apoptosis were reversed in the presence of Akt cDNA or p53 siRNA. These results confirm that PB exhibits anti-cancer activities through the Akt-p53 pathway. Our study not only reports for the first time the anti-tumour mechanism of PB, but also suggests that PB is a promising therapeutic agent for use in cancer treatments and that metabolomic approaches provide a new strategy to effectively explore the molecular mechanisms of promising anticancer compounds.
Highlights
PB decreased the proliferation of hepatocellular carcinoma cells
When the LO2 cells were treated with PB (0.5–8 μM), the inhibition rates were lower than 20%, suggesting a selective proliferation inhibition of PB on cancer cells (Fig. 1B)
To further confirm the effect of PB on cell proliferation, an EdU incorporation assay was conducted, and we observed that PB significantly reduced the number of EdU-positive cells compared with number in the dimethyl sulfoxide (DMSO) treated group in a dose-dependent manner (Fig. 1E)
Summary
The emerging field of metabolome analysis promises immense potential for biomarker discovery and the exploration of molecular mechanisms in perturbed systems related to diseases, providing a rapid way to look for targeted molecular markers and pathways[11]. Withanolides have attracted much scientific attention due to their structural features and important pharmacological activities such as antimicrobial, anticancer, anti-inflammatory, and immunomodulatory effects[12,13,14]. We report for the first time on the anti-tumour mechanism of PB and the application of metabolomics during the process of exploring the molecular mechanism of the antitumour activity of PB. Our results demonstrate that metabolomics is an effective method for exploring the complex mechanisms of natural products and that PB induces apoptosis and a decrease in the level of glycolysis through the Akt-p53 pathway
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