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...
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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]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	LIM kinase CEL_Amide ALL tyrosine kinase inhibitors

Übergeordnetes Werk:	In: Journal of Clinical Medicine - MDPI AG, 2013, 11(2022), 22, p 6761
Übergeordnetes Werk:	volume:11 ; year:2022 ; number:22, p 6761

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/jcm11226761

Katalog-ID:	DOAJ025826220

Internformat


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100	0		\|a Jeannig Berrou \|e verfasserin \|4 aut
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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700	0		\|a Hanane Djamai \|e verfasserin \|4 aut
700	0		\|a Emilie Adicéam \|e verfasserin \|4 aut
700	0		\|a Véronique Parietti \|e verfasserin \|4 aut
700	0		\|a Anna Kaci \|e verfasserin \|4 aut
700	0		\|a Emmanuelle Clappier \|e verfasserin \|4 aut
700	0		\|a Jean-Michel Cayuela \|e verfasserin \|4 aut
700	0		\|a André Baruchel \|e verfasserin \|4 aut
700	0		\|a Fabrice Paublant \|e verfasserin \|4 aut
700	0		\|a Renaud Prudent \|e verfasserin \|4 aut
700	0		\|a Jacques Ghysdael \|e verfasserin \|4 aut
700	0		\|a Claude Gardin \|e verfasserin \|4 aut
700	0		\|a Hervé Dombret \|e verfasserin \|4 aut
700	0		\|a Thorsten Braun \|e verfasserin \|4 aut
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912			\|a GBV_ILN_73
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912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
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912			\|a GBV_ILN_170
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912			\|a GBV_ILN_213
912			\|a GBV_ILN_230
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
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912			\|a GBV_ILN_2005
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912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4322
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912			\|a GBV_ILN_4324
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912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4367
912			\|a GBV_ILN_4700
951			\|a AR
952			\|d 11 \|j 2022 \|e 22, p 6761

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publishDate	2022
allfields	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
allfieldsGer	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
allfieldsSound	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
language	English
source	In Journal of Clinical Medicine 11(2022), 22, p 6761 volume:11 year:2022 number:22, p 6761
sourceStr	In Journal of Clinical Medicine 11(2022), 22, p 6761 volume:11 year:2022 number:22, p 6761
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	LIM kinase CEL_Amide <i<BCR::ABL</i< ALL tyrosine kinase inhibitors Medicine R
isfreeaccess_bool	true
container_title	Journal of Clinical Medicine
authorswithroles_txt_mv	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@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	718632478
id	DOAJ025826220
language_de	englisch
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author	Jeannig Berrou
spellingShingle	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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topic_title	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
topic	misc LIM kinase misc CEL_Amide misc <i<BCR::ABL</i< misc ALL misc tyrosine kinase inhibitors misc Medicine misc R
topic_unstemmed	misc LIM kinase misc CEL_Amide misc <i<BCR::ABL</i< misc ALL misc tyrosine kinase inhibitors misc Medicine misc R
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title	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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title_full	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)
author_sort	Jeannig Berrou
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author_browse	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
container_volume	11
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author-letter	Jeannig Berrou
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author2-role	verfasserin
title_sort	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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title_short	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)
url	https://doi.org/10.3390/jcm11226761 https://doaj.org/article/b8ef5dd2b6894ca7b53f74bb99898a4a https://www.mdpi.com/2077-0383/11/22/6761 https://doaj.org/toc/2077-0383
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score	7.3981476

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ABL+</i<) Acute Lymphoblastic Leukemia (ALL)

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