Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB signaling pathway in lung cancer cells

Yu, Zhenlong; Guo, Wei; Ma, Xiaochi; Zhang, Baojing; Dong, Peipei; Huang, Lin; Wang, Xiuli; Huo, Xiaokui; Yu, Wei; Yi, Canhui; Xiao, Yao; Yang, Wenjing; Yu, Qin; Yuan, Yuhui; Shao, Meng; Liu, Quentin; Deng, Wu

doi:10.1186/1476-4598-13-203

Cited by 75 publications

(73 citation statements)

References 46 publications

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“…The immunofluorescence staining assay was performed as previously described (48). In brief, cells were cultured in chamber slides at a density of 2 × 10 5 cells/well.…”

Section: Confocal Microscopymentioning

confidence: 99%

Metabolic Profile of 3-Acetyl-11-Keto-β-Boswellic Acid and 11-Keto-β-Boswellic Acid in Human Preparations In Vitro, Species Differences, and Bioactivity Variation

Cui

Tian

Ning

et al. 2016

AAPS J

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3-Acetyl-11-keto-β-boswellic acid (AKBA) and 11-keto-β-boswellic acid (KBA) are widely used in the clinic as anti-inflammatory drugs. However, these drugs have the poor bioavailability, which may be caused by their extensive metabolism. In this study, we systemically characterized both phase I and II metabolism of AKBA and KBA in vitro. In total, four major metabolites were firstly biosynthesized and identified using 1D and 2D NMR spectroscopy. Among them, three metabolites were novel. The kinetic parameters (K m , V max , CL int, and K i ) were also analyzed systematically in various biological samples. Finally, the deacetylation of AKBA and hydroxylation of KBA were confirmed to be the major metabolic pathways based on their large CL int and the high amounts of KBA (46.7%) and hydroxylated KBA (50.8%) along with a low amount of AKBA (2.50%) in human primary hepatocytes. Carboxylesterase 2 (CE2) selectively catalyzed the deacetylation of AKBA to form KBA. Although CYP3A4, CYP3A5, and CYP3A7 catalyzed the metabolism of KBA, CYP3A4 played a predominant role in the hydroxylation reaction of KBA in human. Notably, deacetylation and regioselective hydroxylation exhibited considerable species differences. Deacetylation was only observed in human liver microsomes and primary human hepatocytes; 21- and 20-mono-hydroxylation of KBA were primarily observed in human, monkey, and dog; and 16- and 30-mono-hydroxylation were observed in other species. More importantly, all four mono-hydroxylation metabolites exhibited a moderate anti-inflammatory activity. The 21- and 20-hydroxylation metabolites inhibited the expression of iNOS, the LPS-induced activation of IkBα and p65 phosphorylation, and suppressed p65 nuclear translocation in RAW264.7 cells.

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“…The immunofluorescence staining assay was performed as previously described (48). In brief, cells were cultured in chamber slides at a density of 2 × 10 5 cells/well.…”

Section: Confocal Microscopymentioning

confidence: 99%

Metabolic Profile of 3-Acetyl-11-Keto-β-Boswellic Acid and 11-Keto-β-Boswellic Acid in Human Preparations In Vitro, Species Differences, and Bioactivity Variation

Cui

Tian

Ning

et al. 2016

AAPS J

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“…These interacting proteins include the ribosome proteins, RNA transport proteins, apoptotic proteins and metabolic process proteins. It is interesting to note that the transcription factor NF-κB, was also observed in the network, which was reported as the potential target of CS-6 in our previous work [9]. …”

Section: Resultsmentioning

confidence: 81%

“…Our previous experiment found that CS-6 could significantly decrease tumor volume and weight compared the control group without obvious toxic effects in mice [9]. Moreover, the immunohistochemical staining assay was used to determine the expression of Hsp90 in tumor issues.…”

Section: Resultsmentioning

confidence: 99%

“…Hsp90 client protein Akt, which promotes transcription of pro-survival genes, triggers NF-κB activation by regulating κB kinase (IKK) [23, 24]. Our early study had shown that CS-6 also decreased the expression levels of p-IκB-α and p-IKKβ, and inhibited translocation of the NF-κB p65/p50 proteins from cell cytoplasm to nucleus compared with control group [9]. These results indicated that CS-6 might be a potential Hsp90 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…Several in vitro and in vivo studies have demonstrated anti-cancer effects of bufadienolides in various cancers [7, 8]. Gamabufotalin (CS-6), a major derivative of bufadienolides, has shown significant anti-tumor activity, with stable metabolic properties and less adverse effects in previous work [9–11], compared with other bufadienolides. However, as a bioactive molecular, the key signal pathways underlying the anti-cancer mechanism, and the therapeutic targets of CS-6 had not yet been well characterized.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative proteomics reveals molecular mechanism of gamabufotalin and its potential inhibition on Hsp90 in lung cancer

Zhang

Wang

et al. 2016

Oncotarget

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Gamabufotalin (CS-6) is a major bufadienolide of Chansu, which shows desirable metabolic stability and less adverse effect in cancer therapy. CS-6 treatment inhibited the proliferation of NSCLC in a nanomolar range. And CS-6 could induce G2/M cell cycle arrest and apoptosis in A549 cells. However, its molecular mechanism in antitumor activity remains poorly understood. We employed a quantitative proteomics approach to identify the potential cellular targets of CS-6, and found 38 possible target-related proteins. Among them, 31 proteins were closely related in the protein-protein interaction network. One of the regulatory nodes in key pathways was occupied by Hsp90. Molecular docking revealed that CS-6 interacted with the ATP-binding sites of Hsp90. In addition, CS-6 inhibited the chaperone function of Hsp90 and reduced expression of Hsp90-dependent client proteins. Moreover, CS-6 markedly down-regulated the protein level of Hsp90 in tumor tissues of the xenograft mice. Taken together, our results suggest that CS-6 might be a novel inhibitor of Hsp90, and the possible network associated with CS-6 target-related proteins was constructed, which provided experimental evidence for the preclinical value of using CS-6 as an effective antitumor agent in treatment of NSCLC.

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Isoalantolactone inhibits IKKβ kinase activity to interrupt the NF‐κB/COX‐2‐mediated signaling cascade and induces apoptosis regulated by the mitochondrial translocation of cofilin in glioblastoma

et al. 2019

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Isoalantolactone (IATL), a sesquiterpene lactone compound, possesses many pharmacological and biological activities, but its role in glioblastoma (GBM) treatment is still unknown. The aim of the current study was to investigate the antiglioma effects of IATL and to explore the underlying molecular mechanisms. In the current study, the biological functions of IATL were examined by MTT, cell migration, colony formation, and cell apoptosis assays. Confocal immunofluorescence techniques, chromatin immunoprecipitation, and pull‐down assays were used to explore the precise underlying molecular mechanisms. To examine IATL activity and the molecular mechanisms by which it inhibits glioma growth in vivo, we used a xenograft tumor mouse model. Furthermore, Western blotting was used to confirm the changes in protein expression after IATL treatment. According to the results, IATL inhibited IKKβ phosphorylation, thus inhibiting both the binding of NF‐κB to the cyclooxygenase 2 (COX‐2) promoter and the recruitment of p300 and eventually inhibiting COX‐2 expression. In addition, IATL induced glioma cell apoptosis by promoting the conversion of F‐actin to G‐actin, which in turn activates the cytochrome c (Cyt c) and caspase‐dependent apoptotic pathways. In the animal experiments, IATL reduced the size and weight of glioma tumors in xenograft mice and inhibited the expression of COX‐2 and phosphorylated NF‐κB p65 in the transplanted tumors. In conclusion, the current study indicated that IATL inhibited the expression of COX‐2 through the NF‐κB signaling pathway and induced the apoptosis of glioma cells by increasing actin transformation. These results suggested that IATL could be greatly effective in GBM treatment.

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Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB signaling pathway in lung cancer cells

Cited by 75 publications

References 46 publications

Metabolic Profile of 3-Acetyl-11-Keto-β-Boswellic Acid and 11-Keto-β-Boswellic Acid in Human Preparations In Vitro, Species Differences, and Bioactivity Variation

Metabolic Profile of 3-Acetyl-11-Keto-β-Boswellic Acid and 11-Keto-β-Boswellic Acid in Human Preparations In Vitro, Species Differences, and Bioactivity Variation

Quantitative proteomics reveals molecular mechanism of gamabufotalin and its potential inhibition on Hsp90 in lung cancer

Isoalantolactone inhibits IKKβ kinase activity to interrupt the NF‐κB/COX‐2‐mediated signaling cascade and induces apoptosis regulated by the mitochondrial translocation of cofilin in glioblastoma

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