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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-05-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.579488/full |
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| author | Atef Nehdi Atef Nehdi Atef Nehdi Nosaibah Samman Nosaibah Samman Abdullah Mashhour Abdullah Mashhour Alshaimaa Alhallaj Alshaimaa Alhallaj Thadeo Trivilegio Thadeo Trivilegio Sheraz Gul Jeanette Reinshagen Ahmed Alaskar Ahmed Alaskar Ahmed Alaskar Gamal Gmati Gamal Gmati Khadega A. Abuelgasim Khadega A. Abuelgasim Fatmah Mansour Fatmah Mansour Mohamed Boudjelal Mohamed Boudjelal |
| author_facet | Atef Nehdi Atef Nehdi Atef Nehdi Nosaibah Samman Nosaibah Samman Abdullah Mashhour Abdullah Mashhour Alshaimaa Alhallaj Alshaimaa Alhallaj Thadeo Trivilegio Thadeo Trivilegio Sheraz Gul Jeanette Reinshagen Ahmed Alaskar Ahmed Alaskar Ahmed Alaskar Gamal Gmati Gamal Gmati Khadega A. Abuelgasim Khadega A. Abuelgasim Fatmah Mansour Fatmah Mansour Mohamed Boudjelal Mohamed Boudjelal |
| author_sort | Atef Nehdi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-16T23:20:31Z |
| format | Article |
| id | doaj.art-e03ead364a234de5b30b7dc5cfc17ce4 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-16T23:20:31Z |
| publishDate | 2021-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e03ead364a234de5b30b7dc5cfc17ce42022-12-21T22:12:11ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-05-011110.3389/fonc.2021.579488579488A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia TreatmentAtef Nehdi0Atef Nehdi1Atef Nehdi2Nosaibah Samman3Nosaibah Samman4Abdullah Mashhour5Abdullah Mashhour6Alshaimaa Alhallaj7Alshaimaa Alhallaj8Thadeo Trivilegio9Thadeo Trivilegio10Sheraz Gul11Jeanette Reinshagen12Ahmed Alaskar13Ahmed Alaskar14Ahmed Alaskar15Gamal Gmati16Gamal Gmati17Khadega A. Abuelgasim18Khadega A. Abuelgasim19Fatmah Mansour20Fatmah Mansour21Mohamed Boudjelal22Mohamed Boudjelal23Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaDepartment of Life Sciences, Faculty of Sciences of Gabes, University of Gabes, Gabes, TunisiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaFraunhofer Institute for Molecular Biology and Applied Ecology IME-ScreeningPort, Hamburg, GermanyFraunhofer Institute for Molecular Biology and Applied Ecology IME-ScreeningPort, Hamburg, GermanyMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaDivision of Hematology & HCT, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi ArabiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaDivision of Hematology & HCT, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi ArabiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaDivision of Hematology & HCT, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaMedical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi ArabiaKing Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi ArabiaDrug 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.https://www.frontiersin.org/articles/10.3389/fonc.2021.579488/fullCLLfludarabineIsoprenalineATP depletionsynergistic effectIbrutinib |
| spellingShingle | Atef Nehdi Atef Nehdi Atef Nehdi Nosaibah Samman Nosaibah Samman Abdullah Mashhour Abdullah Mashhour Alshaimaa Alhallaj Alshaimaa Alhallaj Thadeo Trivilegio Thadeo Trivilegio Sheraz Gul Jeanette Reinshagen Ahmed Alaskar Ahmed Alaskar Ahmed Alaskar Gamal Gmati Gamal Gmati Khadega A. Abuelgasim Khadega A. Abuelgasim Fatmah Mansour Fatmah Mansour Mohamed Boudjelal Mohamed Boudjelal A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment Frontiers in Oncology CLL fludarabine Isoprenaline ATP depletion synergistic effect Ibrutinib |
| 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 | CLL fludarabine Isoprenaline ATP depletion synergistic effect Ibrutinib |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.579488/full |
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