Combined inhibition of BCR-ABL1 and the proteasome as a potential novel therapeutic approach in BCR-ABL positive acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is a disease of lymphoid progenitor cells with an often aggressive course and is commonly caused by the BCR-ABL fusion gene t(9;22) in adults. This fusion gene encodes a constitutively active tyrosine kinase that can be effectively inhibited by tyrosine kinase inhi...
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| creator | Maletzke, Saskia Salimi, Azam Vieri, Margherita Schroeder, Kema Marlen Schemionek, Mirle Masouleh, Behzad Kharabi Brümmendorf, Tim H Koschmieder, Steffen Appelmann, Iris |
| description | Acute lymphoblastic leukemia (ALL) is a disease of lymphoid progenitor cells with an often aggressive course and is commonly caused by the BCR-ABL fusion gene t(9;22) in adults. This fusion gene encodes a constitutively active tyrosine kinase that can be effectively inhibited by tyrosine kinase inhibitors (TKIs), with imatinib being the paradigmatic agent of this class. However, BCR-ABL+ ALL cells rapidly develop mutations against many of the available TKIs, and consecutive disease relapse still results in an overall unfavorable prognosis for patients with this disease. To date, allogeneic stem cell transplantation is the only known curative therapeutic option for the mostly elderly patients with BCR-ABL+ ALL. The discrepancy between the limited therapeutic armamentarium and the growing therapeutic need in an aging population is therefore a reason to test drug combinations against BCR-ABL+ ALL. In this study, we demonstrate that the combination of TKIs with proteasome inhibitors efficiently and under certain conditions synergistically exerts cytotoxic effects in BCR-ABL+ ALL cells in vitro with respect to the induction of apoptosis. Both sole and combined treatment of BCR-ABL+ ALL with the proteasome inhibitors bortezomib and ixazomib, respectively, and TKI causes a significantly greater reduction in cell viability than TKI treatment alone in both BCR-ABL+ cell lines TOM-1 and BV-173. In BV-173 cells, we observed a significant reduction in cell viability to only 1.26%±0.46% with bortezomib treatment and 1.57±0.7% with combination treatment, whereas cells treated with dasatinib alone still had a viable percentage of 40.58±2.6%. Similar results were obtained when ixazomib was applied to both cell lines, and apoptosis was induced in both cases (93.36%±2.7% apoptotic BV-173 cells when treated with ixazomib and TKI). The combination of TKI and proteasome inhibitor is efficient in vitro, potentially expanding the spectrum of therapeutic options for patients with BCR-ABL+ ALL. |
| doi_str_mv | 10.1371/journal.pone.0268352 |
| format | Article |
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This fusion gene encodes a constitutively active tyrosine kinase that can be effectively inhibited by tyrosine kinase inhibitors (TKIs), with imatinib being the paradigmatic agent of this class. However, BCR-ABL+ ALL cells rapidly develop mutations against many of the available TKIs, and consecutive disease relapse still results in an overall unfavorable prognosis for patients with this disease. To date, allogeneic stem cell transplantation is the only known curative therapeutic option for the mostly elderly patients with BCR-ABL+ ALL. The discrepancy between the limited therapeutic armamentarium and the growing therapeutic need in an aging population is therefore a reason to test drug combinations against BCR-ABL+ ALL. In this study, we demonstrate that the combination of TKIs with proteasome inhibitors efficiently and under certain conditions synergistically exerts cytotoxic effects in BCR-ABL+ ALL cells in vitro with respect to the induction of apoptosis. Both sole and combined treatment of BCR-ABL+ ALL with the proteasome inhibitors bortezomib and ixazomib, respectively, and TKI causes a significantly greater reduction in cell viability than TKI treatment alone in both BCR-ABL+ cell lines TOM-1 and BV-173. In BV-173 cells, we observed a significant reduction in cell viability to only 1.26%±0.46% with bortezomib treatment and 1.57±0.7% with combination treatment, whereas cells treated with dasatinib alone still had a viable percentage of 40.58±2.6%. Similar results were obtained when ixazomib was applied to both cell lines, and apoptosis was induced in both cases (93.36%±2.7% apoptotic BV-173 cells when treated with ixazomib and TKI). The combination of TKI and proteasome inhibitor is efficient in vitro, potentially expanding the spectrum of therapeutic options for patients with BCR-ABL+ ALL.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0268352</identifier><identifier>PMID: 36194587</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Abl protein ; Acute lymphoblastic leukemia ; Acute lymphocytic leukemia ; Aging ; Apoptosis ; BCR protein ; BCR-ABL protein ; BCR-ABL tyrosine kinase inhibitors ; Biology and Life Sciences ; Bortezomib ; Cell cycle ; Cell growth ; Cell viability ; Chemotherapy ; Chemotherapy, Combination ; Chromosomes ; Combined treatment ; Cytotoxicity ; Development and progression ; Disease ; Drug therapy ; Drugs ; Fusion protein ; Genetic aspects ; Geriatrics ; Imatinib ; Inhibitors ; Kinases ; Leukemia ; Lymphatic leukemia ; Medical prognosis ; Medicine and Health Sciences ; Multiple myeloma ; Mutation ; Older people ; Patients ; Physical Sciences ; Progenitor cells ; Proteasome inhibitors ; Protein-tyrosine kinase ; Proteins ; Reduction ; Research and Analysis Methods ; Stem cell transplantation ; Stem cells ; Transplantation ; Tyrosine</subject><ispartof>PloS one, 2022-10, Vol.17 (10), p.e0268352-e0268352</ispartof><rights>COPYRIGHT 2022 Public Library of Science</rights><rights>2022 Maletzke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 Maletzke et al 2022 Maletzke et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c599t-a7be16f71fad8fd620a19ab610d883d7c171995db8457914526308b23c8b0bee3</citedby><cites>FETCH-LOGICAL-c599t-a7be16f71fad8fd620a19ab610d883d7c171995db8457914526308b23c8b0bee3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531817/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531817/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids></links><search><contributor>Dello Sbarba, Persio</contributor><creatorcontrib>Maletzke, Saskia</creatorcontrib><creatorcontrib>Salimi, Azam</creatorcontrib><creatorcontrib>Vieri, Margherita</creatorcontrib><creatorcontrib>Schroeder, Kema Marlen</creatorcontrib><creatorcontrib>Schemionek, Mirle</creatorcontrib><creatorcontrib>Masouleh, Behzad Kharabi</creatorcontrib><creatorcontrib>Brümmendorf, Tim H</creatorcontrib><creatorcontrib>Koschmieder, Steffen</creatorcontrib><creatorcontrib>Appelmann, Iris</creatorcontrib><title>Combined inhibition of BCR-ABL1 and the proteasome as a potential novel therapeutic approach in BCR-ABL positive acute lymphoblastic leukemia</title><title>PloS one</title><description>Acute lymphoblastic leukemia (ALL) is a disease of lymphoid progenitor cells with an often aggressive course and is commonly caused by the BCR-ABL fusion gene t(9;22) in adults. 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Both sole and combined treatment of BCR-ABL+ ALL with the proteasome inhibitors bortezomib and ixazomib, respectively, and TKI causes a significantly greater reduction in cell viability than TKI treatment alone in both BCR-ABL+ cell lines TOM-1 and BV-173. In BV-173 cells, we observed a significant reduction in cell viability to only 1.26%±0.46% with bortezomib treatment and 1.57±0.7% with combination treatment, whereas cells treated with dasatinib alone still had a viable percentage of 40.58±2.6%. Similar results were obtained when ixazomib was applied to both cell lines, and apoptosis was induced in both cases (93.36%±2.7% apoptotic BV-173 cells when treated with ixazomib and TKI). The combination of TKI and proteasome inhibitor is efficient in vitro, potentially expanding the spectrum of therapeutic options for patients with BCR-ABL+ ALL.</description><subject>Abl protein</subject><subject>Acute lymphoblastic leukemia</subject><subject>Acute lymphocytic leukemia</subject><subject>Aging</subject><subject>Apoptosis</subject><subject>BCR protein</subject><subject>BCR-ABL protein</subject><subject>BCR-ABL tyrosine kinase inhibitors</subject><subject>Biology and Life Sciences</subject><subject>Bortezomib</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell viability</subject><subject>Chemotherapy</subject><subject>Chemotherapy, Combination</subject><subject>Chromosomes</subject><subject>Combined treatment</subject><subject>Cytotoxicity</subject><subject>Development and progression</subject><subject>Disease</subject><subject>Drug therapy</subject><subject>Drugs</subject><subject>Fusion protein</subject><subject>Genetic aspects</subject><subject>Geriatrics</subject><subject>Imatinib</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Lymphatic leukemia</subject><subject>Medical prognosis</subject><subject>Medicine and Health Sciences</subject><subject>Multiple myeloma</subject><subject>Mutation</subject><subject>Older people</subject><subject>Patients</subject><subject>Physical Sciences</subject><subject>Progenitor cells</subject><subject>Proteasome inhibitors</subject><subject>Protein-tyrosine kinase</subject><subject>Proteins</subject><subject>Reduction</subject><subject>Research and Analysis Methods</subject><subject>Stem cell transplantation</subject><subject>Stem 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inhibition of BCR-ABL1 and the proteasome as a potential novel therapeutic approach in BCR-ABL positive acute lymphoblastic leukemia</title><author>Maletzke, Saskia ; Salimi, Azam ; Vieri, Margherita ; Schroeder, Kema Marlen ; Schemionek, Mirle ; Masouleh, Behzad Kharabi ; Brümmendorf, Tim H ; Koschmieder, Steffen ; Appelmann, Iris</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c599t-a7be16f71fad8fd620a19ab610d883d7c171995db8457914526308b23c8b0bee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Abl protein</topic><topic>Acute lymphoblastic leukemia</topic><topic>Acute lymphocytic leukemia</topic><topic>Aging</topic><topic>Apoptosis</topic><topic>BCR protein</topic><topic>BCR-ABL protein</topic><topic>BCR-ABL tyrosine kinase inhibitors</topic><topic>Biology and Life Sciences</topic><topic>Bortezomib</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell 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cells with an often aggressive course and is commonly caused by the BCR-ABL fusion gene t(9;22) in adults. This fusion gene encodes a constitutively active tyrosine kinase that can be effectively inhibited by tyrosine kinase inhibitors (TKIs), with imatinib being the paradigmatic agent of this class. However, BCR-ABL+ ALL cells rapidly develop mutations against many of the available TKIs, and consecutive disease relapse still results in an overall unfavorable prognosis for patients with this disease. To date, allogeneic stem cell transplantation is the only known curative therapeutic option for the mostly elderly patients with BCR-ABL+ ALL. The discrepancy between the limited therapeutic armamentarium and the growing therapeutic need in an aging population is therefore a reason to test drug combinations against BCR-ABL+ ALL. In this study, we demonstrate that the combination of TKIs with proteasome inhibitors efficiently and under certain conditions synergistically exerts cytotoxic effects in BCR-ABL+ ALL cells in vitro with respect to the induction of apoptosis. Both sole and combined treatment of BCR-ABL+ ALL with the proteasome inhibitors bortezomib and ixazomib, respectively, and TKI causes a significantly greater reduction in cell viability than TKI treatment alone in both BCR-ABL+ cell lines TOM-1 and BV-173. In BV-173 cells, we observed a significant reduction in cell viability to only 1.26%±0.46% with bortezomib treatment and 1.57±0.7% with combination treatment, whereas cells treated with dasatinib alone still had a viable percentage of 40.58±2.6%. Similar results were obtained when ixazomib was applied to both cell lines, and apoptosis was induced in both cases (93.36%±2.7% apoptotic BV-173 cells when treated with ixazomib and TKI). The combination of TKI and proteasome inhibitor is efficient in vitro, potentially expanding the spectrum of therapeutic options for patients with BCR-ABL+ ALL.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>36194587</pmid><doi>10.1371/journal.pone.0268352</doi><tpages>e0268352</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_2721229281 |
| source | DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Abl protein Acute lymphoblastic leukemia Acute lymphocytic leukemia Aging Apoptosis BCR protein BCR-ABL protein BCR-ABL tyrosine kinase inhibitors Biology and Life Sciences Bortezomib Cell cycle Cell growth Cell viability Chemotherapy Chemotherapy, Combination Chromosomes Combined treatment Cytotoxicity Development and progression Disease Drug therapy Drugs Fusion protein Genetic aspects Geriatrics Imatinib Inhibitors Kinases Leukemia Lymphatic leukemia Medical prognosis Medicine and Health Sciences Multiple myeloma Mutation Older people Patients Physical Sciences Progenitor cells Proteasome inhibitors Protein-tyrosine kinase Proteins Reduction Research and Analysis Methods Stem cell transplantation Stem cells Transplantation Tyrosine |
| title | Combined inhibition of BCR-ABL1 and the proteasome as a potential novel therapeutic approach in BCR-ABL positive acute lymphoblastic leukemia |
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