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Brevilin A Isolated from Centipeda minima Induces Apoptosis in Human Gastric Cancer Cells via an Extrinsic Apoptotic Signaling Pathway.

ABSTRACT: Brevilin A, which has anticancer activities against a range of cancers, is an abundant constituent of the medicinal herb Centipeda minima (L.) A. Braun & Asch, which has also been reported to have anticancer activity against breast cancer cells. However, the anticancer activities of C. minima and brevilin A against human gastric cancer have yet to be reported. In this study, we aimed to evaluate the cytotoxicity and molecular basis underlying the anticancer activities of extracts of C. minima (CMX) and brevilin A against human gastric cancer (AGS) cells. We deduced the potential targets and mechanisms underlying the anticancer activity of brevilin A based on a network pharmacology approach. CCND1, CDK4, and BCL2L1 were identified as the key anticancer genes targeted by brevilin A. Cytotoxicity analyses revealed that CMX and brevilin A reduced the viability of AGS cells to levels below 50% (9.73 ± 1.29 µg/mL and 54.69 ± 1.38 μM, respectively). Furthermore, Hoechst 33342, annexin V, and propidium iodide staining and western blot analyses revealed that CMX and brevilin A promoted a significant induction of apoptotic cell death by upregulating the expression of cleaved caspase-8 and cleaved caspase-3 and reducing the ratio of Bax to Bcl-2, which is partially consistent with the findings of our network pharmacology analysis. Collectively, our observations indicate that CMX and brevilin A are novel sources of herbal medicine with potential utility as effective agents for the treatment of gastric cancer.

SUBMITTER: Lee D

PROVIDER: S-EPMC9268799 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Brevilin A Isolated from Centipeda minima Induces Apoptosis in Human Gastric Cancer Cells via an Extrinsic Apoptotic Signaling Pathway.

Lee Dahae D Kwak Hee Jae HJ Kim Byoung Ha BH Kim Dong-Wook DW Kim Hyun Young HY Kim Seung Hyun SH Kang Ki Sung KS

Plants (Basel, Switzerland) 20220623 13

Brevilin A, which has anticancer activities against a range of cancers, is an abundant constituent of the medicinal herb Centipeda minima (L.) A. Braun & Asch, which has also been reported to have anticancer activity against breast cancer cells. However, the anticancer activities of C. minima and brevilin A against human gastric cancer have yet to be reported. In this study, we aimed to evaluate the cytotoxicity and molecular basis underlying the anticancer activities of extracts o ...[more]

PMID: 35807611

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Project description:BackgroundTraditional Chinese medicine (TCM) has been extensively used for neoplasm treatment and has provided many promising therapeutic candidates. We previously found that Centipeda minima (C. minima), a Chinese medicinal herb, showed anti-cancer effects in lung cancer. However, the active components and underlying mechanisms remain unclear. In this study, we used network pharmacology to evaluate C. minima active compounds and molecular mechanisms in lung cancer.MethodsWe screened the TCMSP database for bioactive compounds and their corresponding potential targets. Lung cancer-associated targets were collected from Genecards, OMIM, and Drugbank databases. We then established a drug-ingredients-gene symbols-disease (D-I-G-D) network and a protein-protein interaction (PPI) network using Cytoscape software, and we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses using R software. To verify the network pharmacology results, we then performed survival analysis, molecular docking analysis, as well as in vitro and in vivo experiments.ResultsWe identified a total of 21 C. minima bioactive compounds and 179 corresponding targets. We screened 804 targets related to lung cancer, 60 of which overlapped with C. minima. The top three candidate ingredients identified by D-I-G-D network analysis were quercetin, nobiletin, and beta-sitosterol. PPI network and core target analyses suggested that TP53, AKT1, and MYC are potential therapeutic targets. Moreover, molecular docking analysis confirmed that quercetin, nobiletin, and beta-sitosterol, combined well with TP53, AKT1, and MYC respectively. In vitro experiments verified that quercetin induced non-small cell lung cancer (NSCLC) cell death in a dose-dependent manner. GO and KEGG analyses found 1771 enriched GO terms and 144 enriched KEGG pathways, including a variety of cancer related pathways, the IL-17 signaling pathway, the platinum drug resistance pathway, and apoptosis pathways. Our in vivo experimental results confirmed that a C. minima ethanol extract (ECM) enhanced cisplatin (CDDP) induced cell apoptosis in NSCLC xenografts.ConclusionsThis study revealed the key C. minima active ingredients and molecular mechanisms in the treatment of lung cancer, providing a molecular basis for further C. minima therapeutic investigation.

Project description:Oxidative stress is implicated in the pathogenesis of neurodegeneration and other aging-related diseases. Previous studies have found that the whole herb of Centipeda minima has remarkable antioxidant activities. However, there have been no reports on the neuroprotective effects of C. minima, and the underlying mechanism of its antioxidant properties is unclear. Here, we examined the underlying mechanism of the antioxidant activities of the ethanol extract of C. minima (ECM) both in vivo and in vitro and found that ECM treatment attenuated glutamate and tert-butyl hydroperoxide (tBHP)-induced neuronal death, reactive oxygen species (ROS) production, and mitochondria dysfunction. tBHP-induced phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinases (JNK) was reduced by ECM, and ECM sustained phosphorylation level of extracellular signal regulated kinase (ERK) in SH-SY5Y and PC12 cells. Moreover, ECM induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the upregulation of phase II detoxification enzymes, including heme oxygenase-1 (HO-1), superoxide dismutase-2 (SOD2), and NAD(P)H quinone oxidoreductase-1 (NQO-1) in both two cell types. In a D-galactose (D-gal) and aluminum muriate (AlCl3)-induced neurodegenerative mouse model, administration of ECM improved the learning and memory of mice in the Morris water maze test and ameliorated the effects of neurodegenerative disorders. ECM sustained the expression level of postsynaptic density 95 (PSD95) and synaptophysin (SYN), activated the Nrf2 signaling pathway, and restored the levels of cellular antioxidants in the hippocampus of mice. In addition, four sesquiterpenoids were isolated from C. minima to identify the bioactive components responsible for the antioxidant activity of C. minima; 6-O-angeloylplenolin and arnicolide D were found to be the active compounds responsible for the activation of the Nrf2 signaling pathway and inhibition of ROS production. Our study examined the mechanism of C. minima and its active components in the amelioration of oxidative stress, which holds the promise for the treatment of neurodegenerative disease.

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Brevilin A Isolated from Centipeda minima Induces Apoptosis in Human Gastric Cancer Cells via an Extrinsic Apoptotic Signaling Pathway.

Publications

Brevilin A Isolated from <i>Centipeda minima</i> Induces Apoptosis in Human Gastric Cancer Cells via an Extrinsic Apoptotic Signaling Pathway.

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