Abstract:
:The concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already-approved drugs to target key factors involved in human diseases. Herein, we used an in silico target prediction algorithm to investigate the mechanism of action of mebendazole, an antihelminthic drug, currently repurposed in the treatment of brain tumors. First, we confirmed that mebendazole decreased the viability of glioblastoma cells in vitro (IC50 values ranging from 288 nm to 2.1 µm). Our in silico approach unveiled 21 putative molecular targets for mebendazole, including 12 proteins significantly upregulated at the gene level in glioblastoma as compared to normal brain tissue (fold change > 1.5; P < 0.0001). Validation experiments were performed on three major kinases involved in cancer biology: ABL1, MAPK1/ERK2, and MAPK14/p38α. Mebendazole could inhibit the activity of these kinases in vitro in a dose-dependent manner, with a high potency against MAPK14 (IC50 = 104 ± 46 nm). Its direct binding to MAPK14 was further validated in vitro, and inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consistent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus highlighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological targeting of MAPK14 in brain tumors. It also opens new avenues for the development of novel MAPK14/p38α inhibitors to treat human diseases.
journal_name
Mol Oncoljournal_title
Molecular oncologyauthors
Ariey-Bonnet J,Carrasco K,Le Grand M,Hoffer L,Betzi S,Feracci M,Tsvetkov P,Devred F,Collette Y,Morelli X,Ballester P,Pasquier Edoi
10.1002/1878-0261.12810subject
Has Abstractpub_date
2020-12-01 00:00:00pages
3083-3099issue
12eissn
1574-7891issn
1878-0261journal_volume
14pub_type
杂志文章abstract::Angiogenin (ANG), a 14-kDa pro-angiogenic secreted protein, has been shown to play a role in cell migration and tumor invasion, which involve proteolytic cleavage of plasminogen to generate plasmin. However, the mechanism by which ANG regulates plasmin formation and cell migration was not known. Our studies here detec...
journal_title:Molecular oncology
pub_type: 杂志文章
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abstract::Autophagy, a well-described cellular mechanism for lysosomal degradation of cytoplasmic content, has emerged as a tumour suppression pathway. Recent evidence indicates that the tumour suppressor function of autophagy is mediated by scavenging of damaged oxidative organelles, thereby preventing accumulation of toxic ox...
journal_title:Molecular oncology
pub_type: 杂志文章,评审
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journal_title:Molecular oncology
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journal_title:Molecular oncology
pub_type: 杂志文章
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journal_title:Molecular oncology
pub_type: 杂志文章,评审
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journal_title:Molecular oncology
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12368
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2016.07.010
更新日期:2016-11-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2009.01.006
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journal_title:Molecular oncology
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journal_title:Molecular oncology
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doi:10.1016/j.molonc.2014.01.001
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1016/j.molonc.2015.12.012
更新日期:2016-05-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/1878-0261.12748
更新日期:2020-08-01 00:00:00
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journal_title:Molecular oncology
pub_type: 临床试验,杂志文章,多中心研究
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更新日期:2013-12-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
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更新日期:2014-12-01 00:00:00
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pub_type: 杂志文章
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更新日期:2017-10-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12167
更新日期:2018-04-01 00:00:00
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journal_title:Molecular oncology
pub_type: 杂志文章
doi:10.1002/1878-0261.12879
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journal_title:Molecular oncology
pub_type: 杂志文章
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journal_title:Molecular oncology
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journal_title:Molecular oncology
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journal_title:Molecular oncology
pub_type: 杂志文章
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journal_title:Molecular oncology
pub_type: 杂志文章
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更新日期:2018-04-01 00:00:00
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更新日期:2021-01-01 00:00:00
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pub_type: 杂志文章,评审
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journal_title:Molecular oncology
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pub_type: 杂志文章
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