Brusatol Derivative–34 Attenuates Allergic Airway Inflammation Via Inhibition of the Spleen Tyrosine Kinase Pathway

Ding, Yasi; Tang, Wanjun; Pei, Fei; Fu, Li; Ma, Pei; Bai, Jinye; Lin, Mingbao; Liu, Yun‐Bao; Hou, Qi

doi:10.3389/fphar.2021.587417

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…All these clinical studies have shown that fostamatinib or R406 have generally manageable tolerability with no serious safety risks, so there is great potential for drug repurposing associated with Syk in severe asthma patients, but the target selectivity and effectiveness require further research. Currently, there is growing evidence demonstrating that some Chinese herbal ingredients are effective in treating asthma by suppressing the Syk-mediated inflammatory pathway ( Ding et al, 2021 ; Yang et al, 2021 ). However, due to the unknown specificity of Syk inhibition, a large number of in vivo experiments are still needed.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Spleen Tyrosine Kinase Restores Glucocorticoid Sensitivity to Improve Steroid-Resistant Asthma

et al. 2022

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Background: Regulation or restoration of therapeutic sensitivity to glucocorticoids is important in patients with steroid-resistant asthma. Spleen tyrosine kinase (Syk) is activated at high levels in asthma patients and mouse models, and small-molecule Syk inhibitors such as R406 show potent anti-inflammatory effects in the treatment of immune inflammatory diseases. Several downstream signaling molecules of Syk are involved in the glucocorticoid response, so we hypothesized that R406 could restore sensitivity to dexamethasone in severe steroid-resistant asthma.Objective: To discover the role of the Syk inhibitor R406 in glucocorticoid resistance in severe asthma.Methods: Steroid-resistant asthma models were induced by exposure of C57BL/6 mice to house dust mite (HDM) and β-glucan and by TNF-α administration to the bronchial epithelial cell line BEAS-2B. We evaluated the role of the Syk inhibitor R406 in dexamethasone (Dex)-insensitive airway inflammation. Pathological alterations and cytokines in the lung tissues and inflammatory cells in BALF were assessed. We examined the effects of Dex or R406 alone and in combination on the phosphorylation of MAPKs, glucocorticoid receptor (GR) and Syk, as well as the transactivation and transrepression induced by Dex in mouse lung tissues and BEAS-2B cells.Results: Exposure to HDM and β-glucan induced steroid-resistant airway inflammation. The Syk inhibitor R406 plus Dex significantly reduced airway inflammation compared with Dex alone. Additionally, TNF-α-induced IL-8 production in BEAS-2B cells was not completely inhibited by Dex, while R406 markedly promoted the anti-inflammatory effect of Dex. Compared with Dex alone, R406 enhanced Dex-mediated inhibition of the phosphorylation of MAPKs and GR-Ser226 induced by allergens or TNF-α in vivo and in vitro. Moreover, R406 also restored the impaired expression and nuclear translocation of GRα induced by TNF-α. Then, the activation of NF-κB and decreased HDAC2 activity in the asthmatic model were further regulated by R406, as well as the expression of GILZ.Conclusions: The Syk inhibitor R406 improves sensitivity to dexamethasone by modulating GR. This study provides a reference for the development of drugs to treat severe steroid-resistant asthma.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Spleen Tyrosine Kinase Restores Glucocorticoid Sensitivity to Improve Steroid-Resistant Asthma

et al. 2022

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“…This translocation and all other rearrangements involving KMT2A are strongly associated with a poor treatment outcome in B-ALL young patients [ 37 ]. Recently, in a study focused on its anti-inflammatory effects, a brusatol derivative was shown to inhibit the spleen tyrosine kinase (SYK) [ 38 ], a kinase whose constitutive activation and associated signaling inhibition was already demonstrated in B-ALL with KMT2A rearrangements [ 39 ]. These previous results indicate that the observed effect in the KOPN-8 cell line may be related to a brusatol mechanism different than what we observed in T-ALL cell lines, for example, by inducing the inhibition of proteins dysregulated specifically in B-ALL.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation

et al. 2022

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Acute lymphoblastic leukemia (ALL) is one of the most common hematological malignancies at pediatric ages and is characterized by different chromosomal rearrangements and genetic abnormalities involved in the differentiation and proliferation of lymphoid precursor cells. Brusatol is a quassinoid plant extract extensively studied due to its antineoplastic effect through global protein synthesis and nuclear factor erythroid 2-related factor-2 (NRF2) signaling inhibition. NRF2 is the main regulator of cellular antioxidant response and reactive oxygen species (ROS), which plays an important role in oxidative stress regulation. This study aimed to evaluate the effect of brusatol in in vitro models of ALL. KOPN-8 (B-ALL), CEM (T-ALL), and MOLT-4 (T-ALL) cell lines were incubated with increasing concentrations of brusatol, and the metabolic activity was evaluated using the resazurin assay. Flow cytometry was used to evaluate cell death, cell cycle, mitochondrial membrane potential (Δψmit), and to measure ROS and reduced glutathione (GSH) levels. Our results show that brusatol promoted a decrease in metabolic activity in ALL cell lines in a time-, dose-, and cell-line-dependent manner. Brusatol induced a cytostatic effect by cell cycle arrest in G0/G1 in all cell lines; however, cell death mediated by apoptosis was only observed in T-ALL cells. Brusatol leads to an oxidative stress imbalance by the increase in ROS levels, namely, superoxide anion. Redox imbalance and cellular apoptosis induced by brusatol are highly modulated by mitochondria disruption as a decrease in mitochondrial membrane potential is detected. These data suggest that brusatol might represent a new therapeutic approach for acute lymphoblastic leukemia, particularly for ALL T-cell lineage.

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“…Consequently, the Cell Counting Kit-8 (CCK-8, Abcam, Cambridge, UK) was used to assess cell viability pursuant medicine (Li et al, 2019;Zhang et al, 2013). Recent reports indicate that Brusatol induces various biological responses, exerting anti-inflammatory (Ding et al, 2021), antiviral (Li et al, 2019), and antitumor activities (Bovilla et al, 2021;Lu et al, 2022;Wang et al, 2021). Furthermore, a growing number of studies demonstrate the antitumor activities of Brusatol, especially in colorectal cancer (Lu et al, 2022), hepatocellular carcinoma [33341052], breast cancer (Bovilla et al, 2021), and nonsmall cell lung cancer (NSCLC) (Xing et al, 2022) cell lines.…”

Section: Viability Assaymentioning

confidence: 99%

Brusatol inhibits the growth of prostate cancer cells and reduces HIF-1α/VEGF expression and glycolysis under hypoxia

Wang

Dai²,

Yan³

et al. 2022

Qual. Assur. Saf. Crops Foods

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Prostate cancer (PCa) has a high rate of morbidity and mortality, which urges us to find a unique and effective drug for treatment. Brusatol, a triterpenoid-degraded derivative, possesses antitumor activities. However, the significance of Brusatol in prostate cancer has not yet been completely elucidated. Therefore, this study aimed to explore how Brusatol affected prostate cancer cells. DU145 and PC-3 cell lines were chosen as experimental models. After Brusatol was added to relevant cells in culture, CCK-8 and colony formation experiments were used to assess cell viability; apoptosis rates were calculated using flow cytometry; and transwell assays were utilized to assess cell migration and invasion ability. Vimentin, N-cadherin, E-cadherin, zonula occludens-1 (ZO-1), hypoxia-inducible factor 1α (HIF-1α), vascular endothelial growth factor (VEGF), glucose transporter-1 (GLUT1), hexokinase 2 (HK2), and lactate dehydrogenase (LDHA) protein expression were evaluated by western blotting, and glucose consumption in cells was assessed using related equipment. In DU145 and PC-3 cells, Brusatol drastically reduced cell proliferation, promoted apoptosis, hindered migration and invasion. Considerably decreased HIF-1α and VEGF protein levels under hypoxia were detected. Furthermore, the expression of GLUT1, HK2, and LDHA was diminished, resulting in decreased glucose consumption in a Brusatol concentration-dependent manner. These findings demonstrate that Brusatol serves as a potent antitumor drug that suppresses DU145 and PC-3 cancer cell growth, metastasis, and glycolysis. This discovery could provide a possible clinical treatment strategy for prostate cancer.

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Brusatol Derivative–34 Attenuates Allergic Airway Inflammation Via Inhibition of the Spleen Tyrosine Kinase Pathway

Cited by 5 publications

References 25 publications

Inhibition of Spleen Tyrosine Kinase Restores Glucocorticoid Sensitivity to Improve Steroid-Resistant Asthma

Inhibition of Spleen Tyrosine Kinase Restores Glucocorticoid Sensitivity to Improve Steroid-Resistant Asthma

Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation

Brusatol inhibits the growth of prostate cancer cells and reduces HIF-1α/VEGF expression and glycolysis under hypoxia

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