A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment
Identifieur interne : 000824 ( Main/Exploration ); précédent : 000823; suivant : 000825A Drug Repositioning Approach Identifies a Combination of Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment
Auteurs : Atef Nehdi [Arabie saoudite, Tunisie] ; Nosaibah Samman [Arabie saoudite] ; Abdullah Mashhour [Arabie saoudite] ; Alshaimaa Alhallaj [Arabie saoudite] ; Thadeo Trivilegio [Arabie saoudite] ; Sheraz Gul [Allemagne] ; Jeanette Reinshagen [Allemagne] ; Ahmed Alaskar [Arabie saoudite] ; Gamal Gmati [Arabie saoudite] ; Khadega A. Abuelgasim [Arabie saoudite] ; Fatmah Mansour [Arabie saoudite] ; Mohamed Boudjelal [Arabie saoudite]Source :
- Frontiers in Oncology [ 2234-943X ] ; 2021.
Abstract
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.
Url:
DOI: 10.3389/fonc.2021.579488
PubMed: 34123769
PubMed Central: 8195271
Affiliations:
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Compounds as a Potential Regimen for Chronic Lymphocytic Leukemia Treatment</title><author><name sortKey="Nehdi, Atef" sort="Nehdi, Atef" uniqKey="Nehdi A" first="Atef" last="Nehdi">Atef Nehdi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Life Sciences, Faculty of Sciences of Gabes, University of Gabes</institution>,<addr-line>Gabes</addr-line>,<country>Tunisia</country></nlm:aff><country xml:lang="fr">Tunisie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Samman, Nosaibah" sort="Samman, Nosaibah" uniqKey="Samman N" first="Nosaibah" last="Samman">Nosaibah Samman</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mashhour, Abdullah" sort="Mashhour, Abdullah" uniqKey="Mashhour A" first="Abdullah" last="Mashhour">Abdullah Mashhour</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Alhallaj, Alshaimaa" sort="Alhallaj, Alshaimaa" uniqKey="Alhallaj A" first="Alshaimaa" last="Alhallaj">Alshaimaa Alhallaj</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Trivilegio, Thadeo" sort="Trivilegio, Thadeo" uniqKey="Trivilegio T" first="Thadeo" last="Trivilegio">Thadeo Trivilegio</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gul, Sheraz" sort="Gul, Sheraz" uniqKey="Gul S" first="Sheraz" last="Gul">Sheraz Gul</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Fraunhofer Institute for Molecular Biology and Applied Ecology IME-ScreeningPort</institution>,<addr-line>Hamburg</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Reinshagen, Jeanette" sort="Reinshagen, Jeanette" uniqKey="Reinshagen J" first="Jeanette" last="Reinshagen">Jeanette Reinshagen</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Fraunhofer Institute for Molecular Biology and Applied Ecology IME-ScreeningPort</institution>,<addr-line>Hamburg</addr-line>,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Alaskar, Ahmed" sort="Alaskar, Ahmed" uniqKey="Alaskar A" first="Ahmed" last="Alaskar">Ahmed Alaskar</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Division of Hematology & HCT, Department of Oncology, King Abdulaziz Medical City</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gmati, Gamal" sort="Gmati, Gamal" uniqKey="Gmati G" first="Gamal" last="Gmati">Gamal Gmati</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Division of Hematology & HCT, Department of Oncology, King Abdulaziz Medical City</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Abuelgasim, Khadega A" sort="Abuelgasim, Khadega A" uniqKey="Abuelgasim K" first="Khadega A." last="Abuelgasim">Khadega A. Abuelgasim</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Division of Hematology & HCT, Department of Oncology, King Abdulaziz Medical City</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Mansour, Fatmah" sort="Mansour, Fatmah" uniqKey="Mansour F" first="Fatmah" last="Mansour">Fatmah Mansour</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Boudjelal, Mohamed" sort="Boudjelal, Mohamed" uniqKey="Boudjelal M" first="Mohamed" last="Boudjelal">Mohamed Boudjelal</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>King Saud bin Abdulaziz University for Health Sciences</institution>,<addr-line>Riyadh</addr-line>,<country>Saudi Arabia</country></nlm:aff><country xml:lang="fr">Arabie saoudite</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Frontiers in Oncology</title><idno type="eISSN">2234-943X</idno><imprint><date when="2021">2021</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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. <italic>In-vitro</italic> treatment of primary leukemic cells with a combination of Isoprenaline/fludarabine or Isoprenaline/Ibrutinib showed a very high synergistic effect. 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Abuelgasim</name><name sortKey="Abuelgasim, Khadega A" sort="Abuelgasim, Khadega A" uniqKey="Abuelgasim K" first="Khadega A." last="Abuelgasim">Khadega A. Abuelgasim</name><name sortKey="Alaskar, Ahmed" sort="Alaskar, Ahmed" uniqKey="Alaskar A" first="Ahmed" last="Alaskar">Ahmed Alaskar</name><name sortKey="Alaskar, Ahmed" sort="Alaskar, Ahmed" uniqKey="Alaskar A" first="Ahmed" last="Alaskar">Ahmed Alaskar</name><name sortKey="Alaskar, Ahmed" sort="Alaskar, Ahmed" uniqKey="Alaskar A" first="Ahmed" last="Alaskar">Ahmed Alaskar</name><name sortKey="Alhallaj, Alshaimaa" sort="Alhallaj, Alshaimaa" uniqKey="Alhallaj A" first="Alshaimaa" last="Alhallaj">Alshaimaa Alhallaj</name><name sortKey="Alhallaj, Alshaimaa" sort="Alhallaj, Alshaimaa" uniqKey="Alhallaj A" first="Alshaimaa" last="Alhallaj">Alshaimaa Alhallaj</name><name sortKey="Boudjelal, Mohamed" sort="Boudjelal, Mohamed" uniqKey="Boudjelal M" first="Mohamed" last="Boudjelal">Mohamed Boudjelal</name><name sortKey="Boudjelal, Mohamed" sort="Boudjelal, Mohamed" uniqKey="Boudjelal M" first="Mohamed" last="Boudjelal">Mohamed Boudjelal</name><name sortKey="Gmati, Gamal" sort="Gmati, Gamal" uniqKey="Gmati G" first="Gamal" last="Gmati">Gamal Gmati</name><name sortKey="Gmati, Gamal" sort="Gmati, Gamal" uniqKey="Gmati G" first="Gamal" last="Gmati">Gamal Gmati</name><name sortKey="Mansour, Fatmah" sort="Mansour, Fatmah" uniqKey="Mansour F" first="Fatmah" last="Mansour">Fatmah Mansour</name><name sortKey="Mansour, Fatmah" sort="Mansour, Fatmah" uniqKey="Mansour F" first="Fatmah" last="Mansour">Fatmah Mansour</name><name sortKey="Mashhour, Abdullah" sort="Mashhour, Abdullah" uniqKey="Mashhour A" first="Abdullah" last="Mashhour">Abdullah Mashhour</name><name sortKey="Mashhour, Abdullah" sort="Mashhour, Abdullah" uniqKey="Mashhour A" first="Abdullah" last="Mashhour">Abdullah Mashhour</name><name sortKey="Nehdi, Atef" sort="Nehdi, Atef" uniqKey="Nehdi A" first="Atef" last="Nehdi">Atef Nehdi</name><name sortKey="Samman, Nosaibah" sort="Samman, Nosaibah" uniqKey="Samman N" first="Nosaibah" last="Samman">Nosaibah Samman</name><name sortKey="Samman, Nosaibah" sort="Samman, Nosaibah" uniqKey="Samman N" first="Nosaibah" last="Samman">Nosaibah Samman</name><name sortKey="Trivilegio, Thadeo" sort="Trivilegio, Thadeo" uniqKey="Trivilegio T" first="Thadeo" last="Trivilegio">Thadeo Trivilegio</name><name sortKey="Trivilegio, Thadeo" sort="Trivilegio, Thadeo" uniqKey="Trivilegio T" first="Thadeo" last="Trivilegio">Thadeo Trivilegio</name></country><country name="Tunisie"><noRegion><name sortKey="Nehdi, Atef" sort="Nehdi, Atef" uniqKey="Nehdi A" first="Atef" last="Nehdi">Atef Nehdi</name></noRegion></country><country name="Allemagne"><noRegion><name sortKey="Gul, Sheraz" sort="Gul, Sheraz" uniqKey="Gul S" first="Sheraz" last="Gul">Sheraz Gul</name></noRegion><name sortKey="Reinshagen, Jeanette" sort="Reinshagen, Jeanette" uniqKey="Reinshagen J" first="Jeanette" last="Reinshagen">Jeanette Reinshagen</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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