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Anti-Tumor Activity of Cembranoid-Type Diterpenes Isolated from Nicotiana tabacum L.

ABSTRACT: Recently, the incidence of hepatocellular carcinoma has increased worldwide. Cembranoid-type diterpenes (CBDs) from tobacco exhibit good antimicrobial, antitumor, and neuroprotective activities. Therefore, in this study, we isolated CBDs from Nicotiana tabacum L. and evaluated their antitumor activity against hepatoma cell lines. Particularly, the anti-tumor activity of ?-2,7,11-cyprotermine-4,6-diol (?-CBD) was investigated against HepG2, SMMC-7721, and HL-7702 cells. The MTT assay revealed that ?-CBD reduced the formation of cell clones and inhibited the proliferation of hepatocellular carcinoma cells. Morphological observations showed that ?-CBD altered cell morphology and membrane permeability before inducing apoptosis. To further explore the antitumor mechanism of ?-CBD, flow cytometry and transcriptome analysis were performed using HepG2 cells. The results showed that the number of HepG2 cells increased from 10.4% to 29.8%, indicating that ?-CBD inhibits the proliferation of hepatocellular carcinoma cells in the S phase. The gene expression analysis of HepG2 cells treated with ?-CBD showed 3068 genes with altered expression, among which 1289 were upregulated and 1779 were downregulated. Apoptosis induced by these differentially expressed genes might be mediated by the p53-PUMA, PI3K-Akt, and IL-1-NF-?B-IAP pathways. Comprehensively, our study shows that ?-CBD isolated from N. tabacum L. can be potentially used as a natural antitumor agent.

SUBMITTER: Yuan XL

PROVIDER: S-EPMC6406568 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Project description:The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.

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Anti-Tumor Activity of Cembranoid-Type Diterpenes Isolated from Nicotiana tabacum L.

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