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Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action
Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cau...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9452629/ https://www.ncbi.nlm.nih.gov/pubmed/36091760 http://dx.doi.org/10.3389/fphar.2022.952250 |
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author | Daniel, Julio Paulino Mesquita, Felipe Pantoja Da Silva, Emerson Lucena de Souza, Pedro Filho Noronha Lima, Luina Benevides de Oliveira, Lais Lacerda Brasil de Moraes, Maria Elisabete Amaral Moreira-Nunes, Caroline de Fátima Aquino Burbano, Rommel Mario Rodríguez Zanatta, Geancarlo Montenegro, Raquel Carvalho |
author_facet | Daniel, Julio Paulino Mesquita, Felipe Pantoja Da Silva, Emerson Lucena de Souza, Pedro Filho Noronha Lima, Luina Benevides de Oliveira, Lais Lacerda Brasil de Moraes, Maria Elisabete Amaral Moreira-Nunes, Caroline de Fátima Aquino Burbano, Rommel Mario Rodríguez Zanatta, Geancarlo Montenegro, Raquel Carvalho |
author_sort | Daniel, Julio Paulino |
collection | PubMed |
description | Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising “new use” drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life. |
format | Online Article Text |
id | pubmed-9452629 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94526292022-09-09 Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action Daniel, Julio Paulino Mesquita, Felipe Pantoja Da Silva, Emerson Lucena de Souza, Pedro Filho Noronha Lima, Luina Benevides de Oliveira, Lais Lacerda Brasil de Moraes, Maria Elisabete Amaral Moreira-Nunes, Caroline de Fátima Aquino Burbano, Rommel Mario Rodríguez Zanatta, Geancarlo Montenegro, Raquel Carvalho Front Pharmacol Pharmacology Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising “new use” drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life. Frontiers Media S.A. 2022-08-25 /pmc/articles/PMC9452629/ /pubmed/36091760 http://dx.doi.org/10.3389/fphar.2022.952250 Text en Copyright © 2022 Daniel, Mesquita, Da Silva, de Souza, Lima, de Oliveira, de Moraes, Moreira-Nunes, Burbano, Zanatta and Montenegro. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Daniel, Julio Paulino Mesquita, Felipe Pantoja Da Silva, Emerson Lucena de Souza, Pedro Filho Noronha Lima, Luina Benevides de Oliveira, Lais Lacerda Brasil de Moraes, Maria Elisabete Amaral Moreira-Nunes, Caroline de Fátima Aquino Burbano, Rommel Mario Rodríguez Zanatta, Geancarlo Montenegro, Raquel Carvalho Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action |
title | Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action |
title_full | Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action |
title_fullStr | Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action |
title_full_unstemmed | Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action |
title_short | Anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action |
title_sort | anticancer potential of mebendazole against chronic myeloid leukemia: in silico and in vitro studies revealed new insights about the mechanism of action |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9452629/ https://www.ncbi.nlm.nih.gov/pubmed/36091760 http://dx.doi.org/10.3389/fphar.2022.952250 |
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