دورية أكاديمية
أعرض في EDS

High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia.

التفاصيل البيبلوغرافية
العنوان: High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia.
المؤلفون: Wander P; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands; Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands., Arentsen-Peters STCJM; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands., Pinhanҫos SS; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands; CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal., Koopmans B; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands., Dolman MEM; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands., Ariese R; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands; Oncode Institute, Utrecht, Netherlands., Bos FL; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands; Oncode Institute, Utrecht, Netherlands., Castro PG; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands., Jones L; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands., Schneider P; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands., Navarro MG; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands., Molenaar JJ; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands., Rios AC; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands; Oncode Institute, Utrecht, Netherlands., Zwaan CM; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands; Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands., Stam RW; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584CS Utrecht, Netherlands. Electronic address: R.W.Stam@prinsesmaximacentrum.nl.
المصدر: Translational oncology [Transl Oncol] 2021 May; Vol. 14 (5), pp. 101048. Date of Electronic Publication: 2021 Mar 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Neoplasia Press Country of Publication: United States NLM ID: 101472619 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1936-5233 (Print) Linking ISSN: 19365233 NLM ISO Abbreviation: Transl Oncol Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [Ann Arbor, MI] : Neoplasia Press
مستخلص: 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 IC 50 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.
Competing Interests: Declaration of Competing Interest None.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: High-throughput drug library screen; MLL-rearranged AML; Pediatric acute myeloid leukemia; Pyrvinium pamoate
تواريخ الأحداث: Date Created: 20210305 Latest Revision: 20210405
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7933809
DOI: 10.1016/j.tranon.2021.101048
PMID: 33667892
قاعدة البيانات: MEDLINE
الوصف
تدمد:1936-5233
DOI:10.1016/j.tranon.2021.101048