ABL+</i<) Acute Lymphoblastic Leukemia (ALL)
ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly pati...
Ausführliche Beschreibung
Autor*in: |
Jeannig Berrou [verfasserIn] Mélanie Dupont [verfasserIn] Hanane Djamai [verfasserIn] Emilie Adicéam [verfasserIn] Véronique Parietti [verfasserIn] Anna Kaci [verfasserIn] Emmanuelle Clappier [verfasserIn] Jean-Michel Cayuela [verfasserIn] André Baruchel [verfasserIn] Fabrice Paublant [verfasserIn] Renaud Prudent [verfasserIn] Jacques Ghysdael [verfasserIn] Claude Gardin [verfasserIn] Hervé Dombret [verfasserIn] Thorsten Braun [verfasserIn] |
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Format: |
E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2022 |
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Schlagwörter: |
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Übergeordnetes Werk: |
In: Journal of Clinical Medicine - MDPI AG, 2013, 11(2022), 22, p 6761 |
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Übergeordnetes Werk: |
volume:11 ; year:2022 ; number:22, p 6761 |
Links: |
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DOI / URN: |
10.3390/jcm11226761 |
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Katalog-ID: |
DOAJ025826220 |
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245 | 1 | 0 | |a Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) |
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520 | |a Ph+ (<i<BCR::ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by <i<BCR::ABL</i<, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for <i<BCR::ABL</i<-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in <i<BCR::ABL+</i< TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in <i<BCR::ABL+</i< cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and <i<BCR::ABL</i< TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A<sup<ko</sup</<i<BCR::ABL1</i<+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with <i<BCR::ABL</i<-targeting TKIs, showing promising synergy that warrants further investigation. | ||
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10.3390/jcm11226761 doi (DE-627)DOAJ025826220 (DE-599)DOAJb8ef5dd2b6894ca7b53f74bb99898a4a DE-627 ger DE-627 rakwb eng Jeannig Berrou verfasserin aut Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Ph+ (<i<BCR::ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by <i<BCR::ABL</i<, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for <i<BCR::ABL</i<-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in <i<BCR::ABL+</i< TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in <i<BCR::ABL+</i< cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and <i<BCR::ABL</i< TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A<sup<ko</sup</<i<BCR::ABL1</i<+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with <i<BCR::ABL</i<-targeting TKIs, showing promising synergy that warrants further investigation. LIM kinase CEL_Amide <i<BCR::ABL</i< ALL tyrosine kinase inhibitors Medicine R Mélanie Dupont verfasserin aut Hanane Djamai verfasserin aut Emilie Adicéam verfasserin aut Véronique Parietti verfasserin aut Anna Kaci verfasserin aut Emmanuelle Clappier verfasserin aut Jean-Michel Cayuela verfasserin aut André Baruchel verfasserin aut Fabrice Paublant verfasserin aut Renaud Prudent verfasserin aut Jacques Ghysdael verfasserin aut Claude Gardin verfasserin aut Hervé Dombret verfasserin aut Thorsten Braun verfasserin aut In Journal of Clinical Medicine MDPI AG, 2013 11(2022), 22, p 6761 (DE-627)718632478 (DE-600)2662592-1 20770383 nnns volume:11 year:2022 number:22, p 6761 https://doi.org/10.3390/jcm11226761 kostenfrei https://doaj.org/article/b8ef5dd2b6894ca7b53f74bb99898a4a kostenfrei https://www.mdpi.com/2077-0383/11/22/6761 kostenfrei https://doaj.org/toc/2077-0383 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 22, p 6761 |
spelling |
10.3390/jcm11226761 doi (DE-627)DOAJ025826220 (DE-599)DOAJb8ef5dd2b6894ca7b53f74bb99898a4a DE-627 ger DE-627 rakwb eng Jeannig Berrou verfasserin aut Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Ph+ (<i<BCR::ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by <i<BCR::ABL</i<, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for <i<BCR::ABL</i<-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in <i<BCR::ABL+</i< TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in <i<BCR::ABL+</i< cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and <i<BCR::ABL</i< TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A<sup<ko</sup</<i<BCR::ABL1</i<+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with <i<BCR::ABL</i<-targeting TKIs, showing promising synergy that warrants further investigation. LIM kinase CEL_Amide <i<BCR::ABL</i< ALL tyrosine kinase inhibitors Medicine R Mélanie Dupont verfasserin aut Hanane Djamai verfasserin aut Emilie Adicéam verfasserin aut Véronique Parietti verfasserin aut Anna Kaci verfasserin aut Emmanuelle Clappier verfasserin aut Jean-Michel Cayuela verfasserin aut André Baruchel verfasserin aut Fabrice Paublant verfasserin aut Renaud Prudent verfasserin aut Jacques Ghysdael verfasserin aut Claude Gardin verfasserin aut Hervé Dombret verfasserin aut Thorsten Braun verfasserin aut In Journal of Clinical Medicine MDPI AG, 2013 11(2022), 22, p 6761 (DE-627)718632478 (DE-600)2662592-1 20770383 nnns volume:11 year:2022 number:22, p 6761 https://doi.org/10.3390/jcm11226761 kostenfrei https://doaj.org/article/b8ef5dd2b6894ca7b53f74bb99898a4a kostenfrei https://www.mdpi.com/2077-0383/11/22/6761 kostenfrei https://doaj.org/toc/2077-0383 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 22, p 6761 |
allfields_unstemmed |
10.3390/jcm11226761 doi (DE-627)DOAJ025826220 (DE-599)DOAJb8ef5dd2b6894ca7b53f74bb99898a4a DE-627 ger DE-627 rakwb eng Jeannig Berrou verfasserin aut Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Ph+ (<i<BCR::ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by <i<BCR::ABL</i<, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for <i<BCR::ABL</i<-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in <i<BCR::ABL+</i< TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in <i<BCR::ABL+</i< cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and <i<BCR::ABL</i< TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A<sup<ko</sup</<i<BCR::ABL1</i<+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with <i<BCR::ABL</i<-targeting TKIs, showing promising synergy that warrants further investigation. LIM kinase CEL_Amide <i<BCR::ABL</i< ALL tyrosine kinase inhibitors Medicine R Mélanie Dupont verfasserin aut Hanane Djamai verfasserin aut Emilie Adicéam verfasserin aut Véronique Parietti verfasserin aut Anna Kaci verfasserin aut Emmanuelle Clappier verfasserin aut Jean-Michel Cayuela verfasserin aut André Baruchel verfasserin aut Fabrice Paublant verfasserin aut Renaud Prudent verfasserin aut Jacques Ghysdael verfasserin aut Claude Gardin verfasserin aut Hervé Dombret verfasserin aut Thorsten Braun verfasserin aut In Journal of Clinical Medicine MDPI AG, 2013 11(2022), 22, p 6761 (DE-627)718632478 (DE-600)2662592-1 20770383 nnns volume:11 year:2022 number:22, p 6761 https://doi.org/10.3390/jcm11226761 kostenfrei https://doaj.org/article/b8ef5dd2b6894ca7b53f74bb99898a4a kostenfrei https://www.mdpi.com/2077-0383/11/22/6761 kostenfrei https://doaj.org/toc/2077-0383 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 22, p 6761 |
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10.3390/jcm11226761 doi (DE-627)DOAJ025826220 (DE-599)DOAJb8ef5dd2b6894ca7b53f74bb99898a4a DE-627 ger DE-627 rakwb eng Jeannig Berrou verfasserin aut Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Ph+ (<i<BCR::ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by <i<BCR::ABL</i<, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for <i<BCR::ABL</i<-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in <i<BCR::ABL+</i< TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in <i<BCR::ABL+</i< cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and <i<BCR::ABL</i< TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A<sup<ko</sup</<i<BCR::ABL1</i<+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with <i<BCR::ABL</i<-targeting TKIs, showing promising synergy that warrants further investigation. LIM kinase CEL_Amide <i<BCR::ABL</i< ALL tyrosine kinase inhibitors Medicine R Mélanie Dupont verfasserin aut Hanane Djamai verfasserin aut Emilie Adicéam verfasserin aut Véronique Parietti verfasserin aut Anna Kaci verfasserin aut Emmanuelle Clappier verfasserin aut Jean-Michel Cayuela verfasserin aut André Baruchel verfasserin aut Fabrice Paublant verfasserin aut Renaud Prudent verfasserin aut Jacques Ghysdael verfasserin aut Claude Gardin verfasserin aut Hervé Dombret verfasserin aut Thorsten Braun verfasserin aut In Journal of Clinical Medicine MDPI AG, 2013 11(2022), 22, p 6761 (DE-627)718632478 (DE-600)2662592-1 20770383 nnns volume:11 year:2022 number:22, p 6761 https://doi.org/10.3390/jcm11226761 kostenfrei https://doaj.org/article/b8ef5dd2b6894ca7b53f74bb99898a4a kostenfrei https://www.mdpi.com/2077-0383/11/22/6761 kostenfrei https://doaj.org/toc/2077-0383 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 22, p 6761 |
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10.3390/jcm11226761 doi (DE-627)DOAJ025826220 (DE-599)DOAJb8ef5dd2b6894ca7b53f74bb99898a4a DE-627 ger DE-627 rakwb eng Jeannig Berrou verfasserin aut Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Ph+ (<i<BCR::ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by <i<BCR::ABL</i<, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for <i<BCR::ABL</i<-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in <i<BCR::ABL+</i< TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in <i<BCR::ABL+</i< cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and <i<BCR::ABL</i< TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A<sup<ko</sup</<i<BCR::ABL1</i<+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with <i<BCR::ABL</i<-targeting TKIs, showing promising synergy that warrants further investigation. LIM kinase CEL_Amide <i<BCR::ABL</i< ALL tyrosine kinase inhibitors Medicine R Mélanie Dupont verfasserin aut Hanane Djamai verfasserin aut Emilie Adicéam verfasserin aut Véronique Parietti verfasserin aut Anna Kaci verfasserin aut Emmanuelle Clappier verfasserin aut Jean-Michel Cayuela verfasserin aut André Baruchel verfasserin aut Fabrice Paublant verfasserin aut Renaud Prudent verfasserin aut Jacques Ghysdael verfasserin aut Claude Gardin verfasserin aut Hervé Dombret verfasserin aut Thorsten Braun verfasserin aut In Journal of Clinical Medicine MDPI AG, 2013 11(2022), 22, p 6761 (DE-627)718632478 (DE-600)2662592-1 20770383 nnns volume:11 year:2022 number:22, p 6761 https://doi.org/10.3390/jcm11226761 kostenfrei https://doaj.org/article/b8ef5dd2b6894ca7b53f74bb99898a4a kostenfrei https://www.mdpi.com/2077-0383/11/22/6761 kostenfrei https://doaj.org/toc/2077-0383 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022 22, p 6761 |
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Jeannig Berrou @@aut@@ Mélanie Dupont @@aut@@ Hanane Djamai @@aut@@ Emilie Adicéam @@aut@@ Véronique Parietti @@aut@@ Anna Kaci @@aut@@ Emmanuelle Clappier @@aut@@ Jean-Michel Cayuela @@aut@@ André Baruchel @@aut@@ Fabrice Paublant @@aut@@ Renaud Prudent @@aut@@ Jacques Ghysdael @@aut@@ Claude Gardin @@aut@@ Hervé Dombret @@aut@@ Thorsten Braun @@aut@@ |
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Jeannig Berrou misc LIM kinase misc CEL_Amide misc <i<BCR::ABL</i< misc ALL misc tyrosine kinase inhibitors misc Medicine misc R Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) |
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Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) LIM kinase CEL_Amide <i<BCR::ABL</i< ALL tyrosine kinase inhibitors |
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Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) |
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Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) |
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Jeannig Berrou Mélanie Dupont Hanane Djamai Emilie Adicéam Véronique Parietti Anna Kaci Emmanuelle Clappier Jean-Michel Cayuela André Baruchel Fabrice Paublant Renaud Prudent Jacques Ghysdael Claude Gardin Hervé Dombret Thorsten Braun |
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preclinical evaluation of a novel small molecule inhibitor of lim kinases (limk) cel_amide in philadelphia-chromosome positive (<i<bcr::abl+</i<) acute lymphoblastic leukemia (all) |
title_auth |
Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) |
abstract |
Ph+ (<i<BCR::ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by <i<BCR::ABL</i<, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for <i<BCR::ABL</i<-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in <i<BCR::ABL+</i< TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in <i<BCR::ABL+</i< cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and <i<BCR::ABL</i< TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A<sup<ko</sup</<i<BCR::ABL1</i<+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with <i<BCR::ABL</i<-targeting TKIs, showing promising synergy that warrants further investigation. |
abstractGer |
Ph+ (<i<BCR::ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by <i<BCR::ABL</i<, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for <i<BCR::ABL</i<-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in <i<BCR::ABL+</i< TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in <i<BCR::ABL+</i< cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and <i<BCR::ABL</i< TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A<sup<ko</sup</<i<BCR::ABL1</i<+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with <i<BCR::ABL</i<-targeting TKIs, showing promising synergy that warrants further investigation. |
abstract_unstemmed |
Ph+ (<i<BCR::ABL+</i<) B-ALL was considered to be high risk, but recent advances in <i<BCR::ABL</i<-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by <i<BCR::ABL</i<, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for <i<BCR::ABL</i<-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in <i<BCR::ABL+</i< TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in <i<BCR::ABL+</i< cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and <i<BCR::ABL</i< TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2A<sup<ko</sup</<i<BCR::ABL1</i<+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with <i<BCR::ABL</i<-targeting TKIs, showing promising synergy that warrants further investigation. |
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Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (<i<BCR::ABL+</i<) Acute Lymphoblastic Leukemia (ALL) |
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