Cucurbitacin IIa interferes with EGFR-MAPK signaling pathway leads to proliferation inhibition in A549 cells

Zhang, Jie; Song, Yifan; Liang, Yuan; Zou, Haifeng; Zuo, Peng; Mi, Yan; Jing, Siyuan; Li, Tiezhu; Wang, Yongjun; Li, Da; Zhang, Tiehua; Wei, Zhengyi

doi:10.1016/j.fct.2019.110654

Cited by 28 publications

(10 citation statements)

References 43 publications

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“…We have screened the anticancer action by in vitro studies using A549 cell lines as a preliminary evaluation. Some reports are interfering in EGFR [39,40] /VEGFR [41] /ALK [42] /Wnt [43,44] /pathways inhibits the proliferation of A549 cell lines, and with this proof, we have carried the MTT assay. Cucurbitacin [39] and diazole [40] have been reported in proliferation inhibition in A549 cells by interfering EGFR signaling pathway.…”

Section: Discussionmentioning

confidence: 77%

“…Some reports are interfering in EGFR [39,40] /VEGFR [41] /ALK [42] /Wnt [43,44] /pathways inhibits the proliferation of A549 cell lines, and with this proof, we have carried the MTT assay. Cucurbitacin [39] and diazole [40] have been reported in proliferation inhibition in A549 cells by interfering EGFR signaling pathway. A study was performed to evaluate the TNKS small molecule inhibitor XAV939 on the proliferation and migration of lung adenocarcinoma A549 cells and found that XAV939 intervention inhibited A549 cell proliferation [43].…”

Section: Discussionmentioning

confidence: 77%

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Structure-Based Multitargeted Molecular Docking Analysis of Pyrazole-Condensed Heterocyclics Against Lung Cancer

et al. 2021

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Objective: The significant drawbacks of chemotherapy are that it destroys healthy cells, resulting in adverse effects. Hence, there is a need to adopt new techniques to develop cancer-specific chemicals that target the molecular pathways in a non-toxic fashion. This study aims to screen pyrazole-condensed heterocyclics for their anticancer activities and analyse their enzyme inhibitory potentials EGFR, ALK, VEGFR and TNKS receptors. Methods: The structures of the compounds were confirmed by IR, NMR and Mass spectral studies. The in silico techniques applied in this study were molecular docking and pharmacophore modeling to analyse the protein-ligand interactions, as they have a significant role in drug discovery. Drug-likeness properties were assessed by the Lipinski rule of five and ADMET properties. Anticancer activity was performed by in vitro MTT assay on lung cancer cell lines. Results: The results confirm that all the synthesised pyrazole derivatives interacted well with the selected targets showing docking scores above-5 kcal/mol. Pyrazole 2e interacted well with all the four lung cancer targets with its stable binding mode and was found to be potent as per the in vitro reports, followed by compounds 3d and 2d. Pharmacophore modeling exposed the responsible features responsible for the anticancer action. ADMET properties reported that all the compounds were found to have properties within the standard limit. The activity spectra of the pyrazoles predicted that pyrazolopyridines (2a-2e) are more effective against specific receptors such as EGFR, ALK and Tankyrase. Conclusion: Thus, this study suggests that the synthesised pyrazole derivatives can be further investigated to validate their enzyme inhibitory potentials by in vivo studies.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 77%

Structure-Based Multitargeted Molecular Docking Analysis of Pyrazole-Condensed Heterocyclics Against Lung Cancer

et al. 2021

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“…Consistent with our earlier analysis of a separate large natural product dataset [ 29 ], mean logGI50 response to cucurbitacin D was statistically significantly different when comparing cell lines without the BRAF V600E variant (mean = -6.69) to those with this variant (mean = -7.16, unadjusted p value = 5.71 × 10 –7 ; FDR adjusted p value = 7.42 × 10 –5 ). This association suggests that cucurbitacin D may have a role in targeting cancers with BRAF mutations or having an effect on BRAF [ 58 ]. Alternatively, the presence of BRAF V600E in most of the melanoma lines (8 out of 9 melanoma cell lines) may suggest that this INP may have a more general effect on growth inhibition in melanoma.…”

Section: Resultsmentioning

confidence: 99%

Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products

et al. 2022

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Background Indian natural products have been anecdotally used for cancer treatment but with limited efficacy. To better understand their mechanism, we examined the publicly available data for the activity of Indian natural products in the NCI-60 cell line panel. Methods We examined associations of molecular genomic features in the well-characterized NCI-60 cancer cell line panel with in vitro response to treatment with 75 compounds derived from Indian plant-based natural products. We analyzed expression measures for annotated transcripts, lncRNAs, and miRNAs, and protein-changing single nucleotide variants in cancer-related genes. We also examined the similarities between cancer cell line response to Indian natural products and response to reference anti-tumor compounds recorded in a U.S. National Cancer Institute (NCI) Developmental Therapeutics Program database. Results Hierarchical clustering based on cell line response measures identified clustering of Phyllanthus and cucurbitacin products with known anti-tumor agents with anti-mitotic mechanisms of action. Curcumin and curcuminoids mostly clustered together. We found associations of response to Indian natural products with expression of multiple genes, notably including SLC7A11 involved in solute transport and ATAD3A and ATAD3B encoding mitochondrial ATPase proteins, as well as significant associations with functional single nucleotide variants, including BRAF V600E. Conclusion These findings suggest potential mechanisms of action and novel associations of in vitro response with gene expression and some cancer-related mutations that increase our understanding of these Indian natural products.

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“…It was indicated that cucurbitacins have a strong activities in anti‐inflammatory, anti‐cancer, anti‐pyretic, anti‐proliferative and pro‐apoptosis 23,24 . Zhang et al 25 pointed that cucurbitacin IIa effectively represses the proliferation of A549 cells, one of the lung cancer cell lines, through occupying the binding pocket of epidermal growth factor receptor (EGFR) to block the ERGF/MAPK signalling pathway. Moreover, Liu et al confirmed that cucurbitacin A could lead to the DNA damage and cell cycle arrest at G2/M of ovarian cancer cell line, thus to play its anti‐cancer activity.…”

Section: Discussionmentioning

confidence: 99%

Cucurbitacin IIb improved active chromatin‐induced systemic lupus erythematosus via balancing the percentage of Th17 and Treg cells

Dong

et al. 2020

Clin Exp Pharma Physio

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The pathogenesis of systemic lupus erythematosus (SLE) is closely associated with aberrant immune system. Here, the aim of our study was to explore the regulation of cucurbitacin IIb (CuIIb) to Th17/Treg cells in SLE. Compared with normal mice, the percentage of Treg cells was downregulated in SLE mouse model, and Th17 was upregulated. Meantime, the production of Treg‐related transcription factor (foxp3) in SLE model mouse was reduced, and the production of Th17‐related transcription factor (RORγt) was increased. After treatment with CuIIb, the percentage of Treg cells in SLE mice was partly upregulated, and Th17 cells percentage was downregulated. The expression of foxp3 and RORγt in SLE mice were promoted and inhibited by CuIIb treatment, respectively. SLE‐induced kidney injury also was improved by CuIIb treatment. In vitro, we demonstrated again that CuIIb upregulated the percentage of Treg cells in lymphocytes from SLE mice, and downregulated the percentage of Th17 cells. Highly expressed IL‐6 and IL17, and lowly expressed IL‐10 and TGF‐β in lymphocytes from SLE mice were repressed and facilitated by CuIIb treatment, respectively. Overall, our data proved that CuIIb improved kidney injury in SLE mice through balancing the percentage of Th17 and Treg cells. Our data provided a reliable evidence to support the potential of CuIIb in SLE treatment.

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Cucurbitacin IIa interferes with EGFR-MAPK signaling pathway leads to proliferation inhibition in A549 cells

Cited by 28 publications

References 43 publications

Structure-Based Multitargeted Molecular Docking Analysis of Pyrazole-Condensed Heterocyclics Against Lung Cancer

Structure-Based Multitargeted Molecular Docking Analysis of Pyrazole-Condensed Heterocyclics Against Lung Cancer

Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products

Cucurbitacin IIb improved active chromatin‐induced systemic lupus erythematosus via balancing the percentage of Th17 and Treg cells

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Cucurbitacin IIa interferes with EGFR-MAPK signaling pathway leads to proliferation inhibition in A549 cells

Cited by 28 publications

References 43 publications

Structure-Based Multitargeted Molecular Docking Analysis of Pyrazole-Condensed Heterocyclics Against Lung Cancer

Structure-Based Multitargeted Molecular Docking Analysis of Pyrazole-Condensed Heterocyclics Against Lung Cancer

Pharmacogenomics of in vitro response of the NCI-60 cancer cell line panel to Indian natural products

Cucurbitacin IIb improved active chromatin‐induced systemic lupus erythematosus via balancing the percentage of Th17 and Treg cells

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Cucurbitacin IIa interferes with EGFR-MAPK signaling pathway leads to proliferation inhibition in A549 cells