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A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment

Drug repositioning is a promising and powerful innovative strategy in the field of drug discovery. In this study, we screened a compound-library containing 800 Food and Drug Administration approved drugs for their anti-leukemic effect. All screening activities made use of human peripheral blood mono...

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Autores principales: Nehdi, Atef, Samman, Nosaibah, Mashhour, Abdullah, Alhallaj, Alshaimaa, Trivilegio, Thadeo, Gul, Sheraz, Reinshagen, Jeanette, Alaskar, Ahmed, Gmati, Gamal, Abuelgasim, Khadega A., Mansour, Fatmah, Boudjelal, Mohamed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195271/
https://www.ncbi.nlm.nih.gov/pubmed/34123769
http://dx.doi.org/10.3389/fonc.2021.579488
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author Nehdi, Atef
Samman, Nosaibah
Mashhour, Abdullah
Alhallaj, Alshaimaa
Trivilegio, Thadeo
Gul, Sheraz
Reinshagen, Jeanette
Alaskar, Ahmed
Gmati, Gamal
Abuelgasim, Khadega A.
Mansour, Fatmah
Boudjelal, Mohamed
author_facet Nehdi, Atef
Samman, Nosaibah
Mashhour, Abdullah
Alhallaj, Alshaimaa
Trivilegio, Thadeo
Gul, Sheraz
Reinshagen, Jeanette
Alaskar, Ahmed
Gmati, Gamal
Abuelgasim, Khadega A.
Mansour, Fatmah
Boudjelal, Mohamed
author_sort Nehdi, Atef
collection PubMed
description Drug repositioning is a promising and powerful innovative strategy in the field of drug discovery. In this study, we screened a compound-library containing 800 Food and Drug Administration approved drugs for their anti-leukemic effect. All screening activities made use of human peripheral blood mononuclear cells (PBMCs), isolated from healthy or leukemic donors. Compounds with confirmed cytotoxicity were selected and classified in three groups: i) anti-neoplastic compounds which are drugs used in leukemia treatment, ii) compounds known to have an anti-cancer effect and iii) compounds demonstrating an anti-leukemic potential for the first time. The latter group was the most interesting from a drug repositioning perspective and yielded a single compound, namely Isoprenaline which is a non-selective β-adrenergic agonist. Analysis of the cytotoxic effect of this drug indicated that it induces sustainable intracellular ATP depletion leading, over time, to necrotic cell death. We exploited the Isoprenaline-induced intracellular ATP depletion to sensitize primary leukemic cells to fludarabine (purine analogue) and Ibrutinib (Bruton’s tyrosine kinase inhibitor) treatment. In-vitro treatment of primary leukemic cells with a combination of Isoprenaline/fludarabine or Isoprenaline/Ibrutinib showed a very high synergistic effect. These combinations could constitute a new efficient regimen for CLL treatment following successful evaluation in animal models and clinical trials.
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spelling pubmed-81952712021-06-12 A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment Nehdi, Atef Samman, Nosaibah Mashhour, Abdullah Alhallaj, Alshaimaa Trivilegio, Thadeo Gul, Sheraz Reinshagen, Jeanette Alaskar, Ahmed Gmati, Gamal Abuelgasim, Khadega A. Mansour, Fatmah Boudjelal, Mohamed Front Oncol Oncology Drug repositioning is a promising and powerful innovative strategy in the field of drug discovery. In this study, we screened a compound-library containing 800 Food and Drug Administration approved drugs for their anti-leukemic effect. All screening activities made use of human peripheral blood mononuclear cells (PBMCs), isolated from healthy or leukemic donors. Compounds with confirmed cytotoxicity were selected and classified in three groups: i) anti-neoplastic compounds which are drugs used in leukemia treatment, ii) compounds known to have an anti-cancer effect and iii) compounds demonstrating an anti-leukemic potential for the first time. The latter group was the most interesting from a drug repositioning perspective and yielded a single compound, namely Isoprenaline which is a non-selective β-adrenergic agonist. Analysis of the cytotoxic effect of this drug indicated that it induces sustainable intracellular ATP depletion leading, over time, to necrotic cell death. We exploited the Isoprenaline-induced intracellular ATP depletion to sensitize primary leukemic cells to fludarabine (purine analogue) and Ibrutinib (Bruton’s tyrosine kinase inhibitor) treatment. In-vitro treatment of primary leukemic cells with a combination of Isoprenaline/fludarabine or Isoprenaline/Ibrutinib showed a very high synergistic effect. These combinations could constitute a new efficient regimen for CLL treatment following successful evaluation in animal models and clinical trials. Frontiers Media S.A. 2021-05-28 /pmc/articles/PMC8195271/ /pubmed/34123769 http://dx.doi.org/10.3389/fonc.2021.579488 Text en Copyright © 2021 Nehdi, Samman, Mashhour, Alhallaj, Trivilegio, Gul, Reinshagen, Alaskar, Gmati, Abuelgasim, Mansour and Boudjelal 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 Oncology
Nehdi, Atef
Samman, Nosaibah
Mashhour, Abdullah
Alhallaj, Alshaimaa
Trivilegio, Thadeo
Gul, Sheraz
Reinshagen, Jeanette
Alaskar, Ahmed
Gmati, Gamal
Abuelgasim, Khadega A.
Mansour, Fatmah
Boudjelal, Mohamed
A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment
title A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment
title_full A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment
title_fullStr A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment
title_full_unstemmed A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment
title_short A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment
title_sort drug repositioning approach identifies a combination of compounds as a potential regimen for chronic lymphocytic leukemia treatment
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195271/
https://www.ncbi.nlm.nih.gov/pubmed/34123769
http://dx.doi.org/10.3389/fonc.2021.579488
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