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Acetyl-bufalin shows potent efficacy against non-small-cell lung cancer by targeting the CDK9/STAT3 signalling pathway

British journal of cancer, 2021-02, Vol.124 (3), p.645-657 [Peer Reviewed Journal]

The Author(s), under exclusive licence to Cancer Research UK 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;The Author(s), under exclusive licence to Cancer Research UK 2020 ;ISSN: 0007-0920 ;EISSN: 1532-1827 ;DOI: 10.1038/s41416-020-01135-6 ;PMID: 33122847

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Title:
Acetyl-bufalin shows potent efficacy against non-small-cell lung cancer by targeting the CDK9/STAT3 signalling pathway
Author: Yang, Lehe ; Zhou, Feng ; Zhuang, Yan ; Liu, Yanan ; Xu, Lingyuan ; Zhao, Haiyang ; Xiang, Youqun ; Dai, Xuanxuan ; Liu, Zhiguo ; Huang, Xiaoying ; Wang, Liangxing ; Zhao, Chengguang
Subjects: Acute toxicity ; Animals ; Antineoplastic Agents - metabolism ; Antineoplastic Agents - pharmacology ; Apoptosis - drug effects ; Bax protein ; Bufanolides - metabolism ; Bufanolides - pharmacology ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - metabolism ; Caspase-3 ; Cdc2 protein ; Cell Line, Tumor ; Cell proliferation ; Cyclin B1 ; Cyclin-dependent kinase ; Cyclin-dependent kinase 9 ; Cyclin-Dependent Kinase 9 - antagonists & inhibitors ; Cyclin-Dependent Kinase 9 - genetics ; Cyclin-Dependent Kinase 9 - metabolism ; Cyclin-dependent kinases ; DNA microarrays ; Enzyme Inhibitors - pharmacology ; Female ; G2 Phase Cell Cycle Checkpoints - drug effects ; Heterografts ; Humans ; Immunoprecipitation ; Kinases ; Lung cancer ; Lung Neoplasms - drug therapy ; Lung Neoplasms - metabolism ; M Phase Cell Cycle Checkpoints - drug effects ; Mcl-1 protein ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, Nude ; Mice, SCID ; Molecular Docking Simulation ; Non-small cell lung carcinoma ; Pharmacokinetics ; Phosphorylation ; Prodrugs - pharmacology ; Proteomes ; Proteomics ; Rats ; RNA, Small Interfering - genetics ; Signal transduction ; siRNA ; Small cell lung carcinoma ; Stat3 protein ; STAT3 Transcription Factor - antagonists & inhibitors ; STAT3 Transcription Factor - metabolism ; Survivin ; Therapeutic targets ; Tumor cell lines ; Tumors ; Vascular endothelial growth factor ; Xenografts
Is Part Of: British journal of cancer, 2021-02, Vol.124 (3), p.645-657
Description: Cyclin-dependent kinase 9 (CDK9) is a promising prognostic marker and therapeutic target in cancers. Bufalin is an effective anti-tumour agent; however, the clinical application of bufalin is limited due to its high toxicity. Acetyl-bufalin, the bufalin prodrug, was designed and synthesised with higher efficiency and lower toxicity. Three non-small-cell lung cancer (NSCLC) cell lines, a xenograft model and a patient-derived xenograft (PDX) model were used to examine the effects of acetyl-bufalin. CDK9/STAT3 involvement was investigated by knockdown with siRNA, proteome microarray assay, western blot analysis and co-immunoprecipitation experiments. Acute toxicity test and pharmacokinetics (PK) study were conducted to assess the safety and PK. The human NSCLC tissues were analysed to verify high CDK9 expression. We showed that CDK9 induced NSCLC cell proliferation and that this effect was associated with STAT3 activation, specifically an increase in STAT3 phosphorylation and transcription factor activity. Acetyl-bufalin is an effective and safety inhibitor of the CDK9/STAT3 pathway, leading to the impediment of various oncogenic processes in NSCLC. Molecular docking and high-throughput proteomics platform analysis uncovered acetyl-bufalin directly binds to CDK9. Consequently, acetyl-bufalin impaired the complex formation of CDK9 and STAT3, decreased the expressions of P-STAT3, and transcribed target genes such as cyclin B1, CDC2, MCL-1, Survivin, VEGF, BCL2, and it upregulated the expression levels of BAX and caspase-3 activity. Acetyl-bufalin inhibited tumour growth in NSCLC xenograft and PDX models. Acetyl-bufalin is a novel blocker of the CDK9/STAT3 pathway thus may have potential in therapy of NSCLC and other cancers.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 0007-0920
EISSN: 1532-1827
DOI: 10.1038/s41416-020-01135-6
PMID: 33122847
Source: PubMed (Medline)
Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
ProQuest Central

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Acetyl-bufalin shows potent efficacy against non-small-cell lung cancer by targeting the CDK9/STAT3 signalling pathway

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