Brusatol: A potential sensitizing agent for cancer therapy from Brucea javanica

He, Ting; Zhou, Fangli; Su, Anping; Zhang, Yujie; Xing, Zhichao; Li, Mi; Li, Zhihui; Wu, Wenshuang

doi:10.1016/j.biopha.2022.114134

Cited by 16 publications

(11 citation statements)

References 65 publications

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“…Brusatol was first identified in extracts of Brucea sumatrana in 1967, 12 and it turned out to be one of the two components of B. javanica with the highest bioactive potential with regard to anti-cancer effects. 5 Cytotoxic effects of brusatol against cancer cells were first discovered in 1979 for leukemia, 13 and IC 50 values in the low nM range were demonstrated in many different in vitro cancer cell models by now, as summarized by He et al 7 Additionally, in vivo studies of xenograft models supported the anti-cancer activity of brusatol with effective dosages varying between 0.5 and 4 mg/kg body weight in mice. 7 Cytotoxicity and Pro-apoptotic Activity of Brusatol.…”

Section: ■ Results and Discussionmentioning

confidence: 93%

“…5 Cytotoxic effects of brusatol against cancer cells were first discovered in 1979 for leukemia, 13 and IC 50 values in the low nM range were demonstrated in many different in vitro cancer cell models by now, as summarized by He et al 7 Additionally, in vivo studies of xenograft models supported the anti-cancer activity of brusatol with effective dosages varying between 0.5 and 4 mg/kg body weight in mice. 7 Cytotoxicity and Pro-apoptotic Activity of Brusatol. To demonstrate that brusatol is cytotoxically active, A549 cells were treated with the reference compound to assess the cellular viability.…”

Section: ■ Results and Discussionmentioning

confidence: 93%

“…5 Among these, brusatol and bruceine D are the two bioactive compounds, which have been studied most extensively in the context of anti-cancer activity. 5 In vitro as well as in vivo studies showed that these compounds and especially brusatol inhibit cellular and tumor growth and other cancer properties in many different cancer types, like lung, colorectal, liver, and pancreatic cancer, via several different pathways, as reviewed by He et al 7 Additionally, when screening the extracts of 23 Thai herbs for their EGFR-TK inhibitory activity by using a specific EGFR-TK inhibitory assay, 8 we identified the ethanolic extract of the fruits of B. javanica as the second most potent out of the 23 plant extracts. Furthermore, among the tested herb extracts, the B. javanica fruit extract had the highest cytotoxic effect on A549 lung cancer cells, 8 which are known to express EGFR and are sensitive to EGFR-TK inhibitors.…”

Section: ■ Introductionmentioning

confidence: 99%

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Identification of the Brucea javanica Constituent Brusatol as a EGFR-Tyrosine Kinase Inhibitor in a Cell-Free Assay

et al. 2023

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Inhibitors of the tyrosine kinase (TK) activity of the epidermal growth factor receptor (EGFR) are routinely used in cancer therapy. However, there is a need to discover a new TK inhibitor. This study evaluated extracts from Brucea javanica and its components for their potential as novel EGFR-TK inhibitors. The cytotoxic effect of a g aqueous extract and its fractions was assessed by MTT assays with A549 lung cancer cells. The two fractions with the highest cytotoxicity were analyzed by LC/MS and 1H NMR. Brusatol was identified as the main constituent of these fractions, and its cytotoxic and pro-apoptotic activities were confirmed in A549 cells. To elucidate the inhibitory activity of brusatol against EGFR-TK, a specific ADP-GloTM kinase assay was used. In this assay, the IC50 value for EGFR-TK inhibition was 333.1 nM. Molecular dynamic simulations and docking experiments were performed to identify the binding pocket of brusatol to be located in the intracellular TK-domain of EGFR. This study demonstrates that brusatol inhibits EGFR-TK and therefore harbors a potential as a new therapeutic drug for the therapy of EGFR-depending cancers.

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Section: ■ Results and Discussionmentioning

confidence: 93%

Section: ■ Results and Discussionmentioning

confidence: 93%

Section: ■ Introductionmentioning

confidence: 99%

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Identification of the Brucea javanica Constituent Brusatol as a EGFR-Tyrosine Kinase Inhibitor in a Cell-Free Assay

et al. 2023

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“…[28,29] They have anti-tumor, anti-inflammatory, anti-oxidation, and enhancing biological activity. [30][31][32] Studies have shown that the knockdown of CircRNA CDR1as triggers low-dose DB (12.5 μM) -induced gastric cancer cell death, but has little effect on hepatocyte proliferation and apoptosis. [33] Studies have shown that brusatol is a promising anticancer compound that acts as a sensitizer when used in combination with other anticancer regimens by disrupting redox homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Prediction of network pharmacology, molecular docking-based strategy, and vitro assays to determine potential pharmacological mechanism of Dioscoreae bulbiferae and Bruceae fructus against laryngocarcinoma

Wu,

Zhu,

Cao

et al. 2023

Medicine

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Background: Based on network pharmacology, molecular docking, and vitro assays, investigate the probable pharmacological mechanism of Dioscoreae bulbiferae and Bruceae fructus in the treatment of laryngocarcinoma. Methods: The active components and targets of Dioscoreae bulbiferae and Bruceae fructus were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database. Targets linked with laryngocarcinoma were gathered from the GeneCards, DisGeNET, and DrugBank databases. The String database was utilized to build a protein–protein interaction network of common medication and illness targets, after which the core targets were filtered out. The Metascape database served for gene ontology enrichment and Kyoto encyclopedia of genes and genomes pathway analysis of common targets. AutoDock then performed molecular docking between the essential component and the vital target. To investigate the biological effects of diosbulbin B, we assessed the viability of laryngocarcinoma cells after diosbulbin B therapy using the Mahalanobis Taguchi system technique. Following that, we looked at how diosbulbin B affected colony formation after 14 days of culture of treated cells. Flow cytometry was utilized to detect apoptosis in order to examine the influence of diosbulbin B on laryngocarcinoma cell apoptosis. Results: According to a study of the literature, the fundamental components of Dioscoreae bulbiferae and Bruceae fructus in the treatment of laryngocarcinoma include brusatol and diosbulbin B, which may operate on core targets such as cyclin D1, Cyclin Dependent Kinase Inhibitor 1A, and E2F Transcription Factor 1. The significant pathways discovered using Kyoto encyclopedia of genes and genomes enrichment analysis were the phosphoinositide 3-kinase-protein kinase B signaling route, the tumor necrosis factor signaling pathway, and so on. These pathways primarily influence the development and prognosis of laryngeal cancer by controlling cell growth, cell proliferation, angiogenesis, tumorigenesis, and metastasis. The molecular docking studies revealed that the affinity between the heart and crucial targets was robust. The results of vitro assays indicate that diosbulbin B suppressed Hep-2 cell activity in a concentration-dependent manner. Besides, diosbulbin B has powerful antiproliferative properties in Hep-2 cells. Flow cytometry results showed that diosbulbin B promoted laryngocarcinoma cell apoptosis in a concentration-dependent manner. Conclusion: The article delivered a preliminary discussion of the probable mechanism of Dioscoreae bulbiferae and Bruceae fructus in the treatment of laryngocarcinoma, which can serve as a theoretical basis and evidence for subsequent experimental investigation.

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“…Brusatol, a particularly bioactive composition of Brucea javanica, possessed the antitumor function in multiple tumours, 3 including melanoma, 4 head and neck squamous cell carcinoma, 5 pituitary adenoma, 6 nasopharyngeal carcinoma 7 and breast cancer. 8 Our previous study found that brusatol disturbing the RCC progression by PTEN/PI3K/AKT pathway, 9 and we believe brusatol‐associated studies will bring treatment breakthroughs for RCC patients.…”

Section: Introductionmentioning

confidence: 99%

Brusatol enhances MEF2A expression to inhibit RCC progression through the Wnt signalling pathway in renal cell carcinoma

Wang,

Zhou,

Bao

et al. 2023

J Cellular Molecular Medi

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Renal cell carcinoma (RCC) is the most aggressive subtype of kidney tumour with a poor prognosis and an increasing incidence rate worldwide. Brusatol, an essential active ingredient derived from Brucea javanica, exhibits potent antitumour properties. Our study aims to explore a novel treatment strategy for RCC patients. We predicted 37 molecular targets of brusatol based on the structure of brusatol, and MEF2A (Myocyte Enhancer Factor 2A) was selected as our object through bioinformatic analyses. We employed various experimental techniques, including RT‐PCR, western blot, CCK8, colony formation, immunofluorescence, wound healing, flow cytometry, Transwell assays and xenograft mouse models, to investigate the impact of MEF2A on RCC. MEF2A expression was found to be reduced in patients with RCC, indicating a close correlation with MEF2A deubiquitylation. Additionally, the protective effects of brusatol on MEF2A were observed. The overexpression of MEF2A inhibits RCC cell proliferation, invasion and migration. In xenograft mice, MEF2A overexpression in RCC cells led to reduced tumour size compared to the control group. The underlying mechanism involves the inhibition of RCC cell proliferation, invasion, migration and epithelial‐mesenchymal transition (EMT) through the modulation of Wnt/β‐catenin signalling. Altogether, we found that MEF2A overexpression inhibits RCC progression by Wnt/β‐catenin signalling, providing novel insight into diagnosis, treatment and prognosis for RCC patients.

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Brusatol: A potential sensitizing agent for cancer therapy from Brucea javanica

Cited by 16 publications

References 65 publications

Identification of the Brucea javanica Constituent Brusatol as a EGFR-Tyrosine Kinase Inhibitor in a Cell-Free Assay

Identification of the Brucea javanica Constituent Brusatol as a EGFR-Tyrosine Kinase Inhibitor in a Cell-Free Assay

Prediction of network pharmacology, molecular docking-based strategy, and vitro assays to determine potential pharmacological mechanism of Dioscoreae bulbiferae and Bruceae fructus against laryngocarcinoma

Brusatol enhances MEF2A expression to inhibit RCC progression through the Wnt signalling pathway in renal cell carcinoma

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