Please use this identifier to cite or link to this item:
https://hdl.handle.net/10316/105504
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Wander, Priscilla | - |
dc.contributor.author | Arentsen-Peters, Susan T. C. J. M. | - |
dc.contributor.author | Pinhanҫos, Sandra | - |
dc.contributor.author | Koopmans, Bianca | - |
dc.contributor.author | Dolman, M. Emmy M. | - |
dc.contributor.author | Ariese, Rijndert | - |
dc.contributor.author | Bos, Frank L. | - |
dc.contributor.author | Castro, Patricia Garrido | - |
dc.contributor.author | Jones, Luke | - |
dc.contributor.author | Schneider, Pauline | - |
dc.contributor.author | Navarro, Miriam Guillen | - |
dc.contributor.author | Molenaar, Jan J. | - |
dc.contributor.author | Rios, Anne C. | - |
dc.contributor.author | Zwaan, C. Michel | - |
dc.contributor.author | Stam, Ronald W. | - |
dc.date.accessioned | 2023-03-03T09:37:46Z | - |
dc.date.available | 2023-03-03T09:37:46Z | - |
dc.date.issued | 2021-05 | - |
dc.identifier.issn | 1936-5233 | pt |
dc.identifier.uri | https://hdl.handle.net/10316/105504 | - |
dc.description.abstract | Pediatric MLL-rearranged acute myeloid leukemia (AML) has a generally unfavorable outcome, primarily due to relapse and drug resistance. To overcome these difficulties, new therapeutic agents are urgently needed. Yet, implementing novel drugs for clinical use is a time-consuming, laborious, costly and high-risk process. Therefore, we applied a drug-repositioning strategy by screening drug libraries, comprised of >4000 compounds that are mostly FDA-approved, in a high-throughput format on primary MLL-rearranged AML cells. Here we identified pyrvinium pamoate (pyrvinium) as a novel candidate drug effective against MLL-rearranged AML, eliminating all cell viability at <1000 nM. Additional screening of identified drug hits on non-leukemic bone marrow samples, resulted in a decrease in cell viability of ∼50% at 1000 nM pyrvinium, suggesting a therapeutic window for targeting leukemic cells specifically. Validation of pyrvinium on an extensive panel of AML cell lines and primary AML samples showed comparable viabilities as the drug screen data, with pyrvinium achieving IC50 values of <80 nM in these samples. Remarkably, pyrvinium also induced cell toxicity in primary MLL-AF10+ AML cells, an MLL-rearrangement associated with a poor outcome. While pyrvinium is able to inhibit the Wnt pathway in other diseases, this unlikely explains the efficacy we observed as β-catenin was not expressed in the AML cells tested. Rather, we show that pyrvinium co-localized with the mitochondrial stain in cells, and hence may act by inhibiting mitochondrial respiration. Overall, this study shows that pyrvinium is highly effective against MLL-rearranged AML in vitro, and therefore represents a novel potential candidate for further studies in MLL-rearranged AML. | pt |
dc.language.iso | eng | pt |
dc.publisher | Neoplasia Press | pt |
dc.relation | KiKa Foundation | pt |
dc.rights | openAccess | pt |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | pt |
dc.subject | High-throughput drug library screen | pt |
dc.subject | Pyrvinium pamoate | pt |
dc.subject | MLL -rearranged AML | pt |
dc.subject | Pediatric acute myeloid leukemia | pt |
dc.title | High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia | pt |
dc.type | article | - |
degois.publication.firstPage | 101048 | pt |
degois.publication.issue | 5 | pt |
degois.publication.title | Translational Oncology | pt |
dc.peerreviewed | yes | pt |
dc.identifier.doi | 10.1016/j.tranon.2021.101048 | pt |
degois.publication.volume | 14 | pt |
dc.date.embargo | 2021-05-01 | * |
uc.date.periodoEmbargo | 0 | pt |
item.languageiso639-1 | en | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.grantfulltext | open | - |
item.fulltext | Com Texto completo | - |
item.cerifentitytype | Publications | - |
item.openairetype | article | - |
crisitem.author.researchunit | CNC - Center for Neuroscience and Cell Biology | - |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
1-s2.0-S1936523321000401-main.pdf | 1.84 MB | Adobe PDF | View/Open |
SCOPUSTM
Citations
8
checked on Aug 12, 2024
WEB OF SCIENCETM
Citations
7
checked on Aug 2, 2024
Page view(s)
43
checked on Aug 13, 2024
Download(s)
18
checked on Aug 13, 2024
Google ScholarTM
Check
Altmetric
Altmetric
This item is licensed under a Creative Commons License