Abstract
ObjectiveAloperine (ALO), an alkaloid isolated from the leaves of Sophora alopecuroides, has been suggested to exhibit anti-inflammatory and anti-tumor properties and is traditionally used to treat various human diseases, including cancer. However, limited information is available about the mechanisms that determine the anti-tumor activities of ALO.MethodsHerein, through comprehensive bioinformatics methods and in vitro functional analyses, we evaluated the detailed anti-tumor mechanisms of ALO.ResultsUsing the databases Bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine and PubChem Project, we identified the potential targets of ALO. A protein–protein interaction network was constructed to determine the relationship among these probable targets. Functional enrichment analysis revealed that ALO is potentially involved in the induction of apoptosis. In addition, molecular docking demonstrated that ALO expectedly docks into the active pocket of the Bcl2 protein, suggesting Bcl2 as a direct target of ALO. Moreover, western blot and qPCR analysis showed that ALO downregulated Bcl2 expression in human glioma cell lines, SK-N-AS and U118. Using flow cytometry methods, we further confirmed that ALO significantly promotes apoptosis in SK-N-AS and U118 cell lines, similar to the effect induced by ABT-737, a well-known Bcl2 inhibitor. In addition, Bcl-2 overexpression could rescue ALO-induced Bcl-2 inhibition and suppress pro-apoptotic effects in glioma cells.ConclusionTaken together, these findings suggest that the natural agent ALO effectively enhances apoptosis by acting as a potential Bcl2 inhibitor in human glioma cells.
Highlights
Current cancer treatment paradigms, combining radiotherapy and chemotherapy with cytotoxic drugs, are frequently restricted by dose-limiting toxicity and severe adverse effects
Using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, as well as protein–protein interaction (PPI) software, we studied the role and pathways affected by ALO
We suggest that Bcl2 inhibition by ALO induces apoptosis in glioma cells
Summary
Current cancer treatment paradigms, combining radiotherapy and chemotherapy with cytotoxic drugs, are frequently restricted by dose-limiting toxicity and severe adverse effects. Given the ample chemical diversity and plethora of molecular targets, several natural products, such as triptolide, diosmetin, tanshinone and others, are poised to become essential sources for new anti-tumor agents (Wei et al, 2019; Xu et al, 2017; Yan et al, 2018). Aloperine (ALO) is a kind of alkaloid with a unique endocyclic scaffold extracted from the Chinese natural product Sophora alopecuroides. Heretofore, ALO has been reported to exert therapeutic effects against pulmonary hypertension, renal injury and colon cancer (Zimecki, 1987). ALO derivatives with a unique endocyclic scaffold have been designed, synthesized and evaluated as HCV, PD-L1 and HIV-1 entry inhibitors (Dang et al, 2016; Zhang et al, 2019). Analysis demonstrated that ALO suppresses tumorigenesis, suggesting its potential therapeutic use in human cancers and multidrug-resistant cancers
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