Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindo...

Autores
Ge, Yun; Byun, Jung S.; de Luca, Paola; Gueron, Geraldine; Yabe, Idalia M.; Sadiq-Ali, Sara G.; Figg, William D.; Quintero, Jesse; Haggerty, Cynthia M.; Li, Quentin Q.; de Siervi, Adriana; Gardner, Kevin
Año de publicación
2008
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-κB (NF-κB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.
Fil: Ge, Yun. National Cancer Institute; Estados Unidos
Fil: Byun, Jung S.. National Cancer Institute; Estados Unidos
Fil: de Luca, Paola. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Yabe, Idalia M.. National Cancer Institute; Estados Unidos
Fil: Sadiq-Ali, Sara G.. National Cancer Institute; Estados Unidos
Fil: Figg, William D.. National Cancer Institute; Estados Unidos
Fil: Quintero, Jesse. National Cancer Institute; Estados Unidos
Fil: Haggerty, Cynthia M.. National Cancer Institute; Estados Unidos
Fil: Li, Quentin Q.. National Cancer Institute; Estados Unidos
Fil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Gardner, Kevin. National Cancer Institute; Estados Unidos
Materia
Cps49
Flavopiridol
Leucemia
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/71290
Acceder
id CONICETDig_8b35dfcfc412caec25a519682637adb1
oai_identifier_str oai:ri.conicet.gov.ar:11336/71290
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridolGe, YunByun, Jung S.de Luca, PaolaGueron, GeraldineYabe, Idalia M.Sadiq-Ali, Sara G.Figg, William D.Quintero, JesseHaggerty, Cynthia M.Li, Quentin Q.de Siervi, AdrianaGardner, KevinCps49FlavopiridolLeucemiahttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/12-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-κB (NF-κB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.Fil: Ge, Yun. National Cancer Institute; Estados UnidosFil: Byun, Jung S.. National Cancer Institute; Estados UnidosFil: de Luca, Paola. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Yabe, Idalia M.. National Cancer Institute; Estados UnidosFil: Sadiq-Ali, Sara G.. National Cancer Institute; Estados UnidosFil: Figg, William D.. National Cancer Institute; Estados UnidosFil: Quintero, Jesse. National Cancer Institute; Estados UnidosFil: Haggerty, Cynthia M.. National Cancer Institute; Estados UnidosFil: Li, Quentin Q.. National Cancer Institute; Estados UnidosFil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Gardner, Kevin. National Cancer Institute; Estados UnidosAmerican Society for Pharmacology and Experimental Therapeutics2008-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/71290Ge, Yun; Byun, Jung S.; de Luca, Paola; Gueron, Geraldine; Yabe, Idalia M.; et al.; Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 74; 3; 9-2008; 872-8830026-895XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1124/mol.107.040808info:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/74/3/872info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:14:42Zoai:ri.conicet.gov.ar:11336/71290instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:14:42.595CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
title Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
spellingShingle Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
Ge, Yun
Cps49
Flavopiridol
Leucemia
title_short Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
title_full Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
title_fullStr Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
title_full_unstemmed Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
title_sort Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol
dc.creator.none.fl_str_mv Ge, Yun
Byun, Jung S.
de Luca, Paola
Gueron, Geraldine
Yabe, Idalia M.
Sadiq-Ali, Sara G.
Figg, William D.
Quintero, Jesse
Haggerty, Cynthia M.
Li, Quentin Q.
de Siervi, Adriana
Gardner, Kevin
author Ge, Yun
author_facet Ge, Yun
Byun, Jung S.
de Luca, Paola
Gueron, Geraldine
Yabe, Idalia M.
Sadiq-Ali, Sara G.
Figg, William D.
Quintero, Jesse
Haggerty, Cynthia M.
Li, Quentin Q.
de Siervi, Adriana
Gardner, Kevin
author_role author
author2 Byun, Jung S.
de Luca, Paola
Gueron, Geraldine
Yabe, Idalia M.
Sadiq-Ali, Sara G.
Figg, William D.
Quintero, Jesse
Haggerty, Cynthia M.
Li, Quentin Q.
de Siervi, Adriana
Gardner, Kevin
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cps49
Flavopiridol
Leucemia
topic Cps49
Flavopiridol
Leucemia
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-κB (NF-κB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.
Fil: Ge, Yun. National Cancer Institute; Estados Unidos
Fil: Byun, Jung S.. National Cancer Institute; Estados Unidos
Fil: de Luca, Paola. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Yabe, Idalia M.. National Cancer Institute; Estados Unidos
Fil: Sadiq-Ali, Sara G.. National Cancer Institute; Estados Unidos
Fil: Figg, William D.. National Cancer Institute; Estados Unidos
Fil: Quintero, Jesse. National Cancer Institute; Estados Unidos
Fil: Haggerty, Cynthia M.. National Cancer Institute; Estados Unidos
Fil: Li, Quentin Q.. National Cancer Institute; Estados Unidos
Fil: de Siervi, Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina
Fil: Gardner, Kevin. National Cancer Institute; Estados Unidos
description 2-(2,4-Difluoro-phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) is a member of a recently identified class of redox-reactive thalidomide analogs that show selective killing of leukemic cells by increasing intracellular reactive oxygen species (ROS) and targeting multiple transcriptional pathways. Flavopiridol is a semisynthetic flavonoid that inhibits cyclin-dependent kinases and also shows selective lethality against leukemic cells. The purpose of this study is to explore the efficacy and mechanism of action of the combinatorial use of the redox-reactive thalidomide CPS49 and the cyclin-dependent kinase inhibitor flavopiridol as a selective antileukemic therapeutic strategy. In combination, CPS49 and flavopiridol were found to induce selective cytotoxicity associated with mitochondrial dysfunction and elevations of ROS in leukemic cells ranging from additive to synergistic activity at low micromolar concentrations. Highest synergy was observed at the level of ROS generation with a strong correlation between cell-specific cytotoxicity and reciprocal coupling of drug-induced ROS elevation with glutathione depletion. Examination of the transcriptional targeting of CPS49 and flavopiridol combinations reveals that the drugs act in concert to initiate a cell specific transcriptional program that manipulates nuclear factor-κB (NF-κB), E2F-1, and p73 activity to promote enhanced mitochondrial instability by simultaneously elevating the expression of the proapoptotic factors BAX, BAD, p73, and PUMA while depressing expression of the antiapoptotic genes MCL1, XIAP, BCL-xL, SURVIVIN, and MDM2. The coadministration of CPS49 and flavopiridol acts through coordinate targeting of transcriptional pathways that enforce selective mitochondrial dysfunction and ROS elevation and is therefore a promising new therapeutic combination that warrants further preclinical exploration.
publishDate 2008
dc.date.none.fl_str_mv 2008-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/71290
Ge, Yun; Byun, Jung S.; de Luca, Paola; Gueron, Geraldine; Yabe, Idalia M.; et al.; Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 74; 3; 9-2008; 872-883
0026-895X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/71290
identifier_str_mv Ge, Yun; Byun, Jung S.; de Luca, Paola; Gueron, Geraldine; Yabe, Idalia M.; et al.; Combinatorial antileukemic disruption of oxidative homeostasis and mitochondrial stability by the redox reactive thalidomide 2-(2,4-difluoro- phenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione (CPS49) and flavopiridol; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 74; 3; 9-2008; 872-883
0026-895X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1124/mol.107.040808
info:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/74/3/872
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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