2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells

Autores
Cárdenas, Mariano Gonzalo; Blank, Viviana Claudia; Marder, Nora Mariel; Roguin, Leonor Patricia
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The cytotoxic activity of 2´-nitroflavone was evaluated in different haematological cancer cell lines and its mechanism of action was further studied in HL-60 cells. 2´-nitroflavone arrested cell cycle at G2/M phase and induced an apoptotic response characterized by an increase in the sub-G1 fraction of cells, a typical DNA ladder fragmentation, chromatin condensation and the detection of cells stained with Annexin V. Apoptosis was dependent on activation of at least caspase-8, -9 and -3. The involvement of death receptor pathway was indicated by the up-regulation of both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor (DR5). We also showed that 2´-nitroflavone increased expression levels of Bax and induced the release of cytochrome C to cytosol, suggesting the participation of the mitochondria-dependent pathway. When mitogen-activated protein kinases (MAPKs) pathways were studied, it was found that p38 and c-Jun NH2-terminal kinase (JNK) pathways were activated by 2´-nitroflavone in HL-60 cells, whereas phosphorylation levels of extracellular signal-regulated kinases (ERK) 1/2 significantly decreased. In addition, whereas both pharmacological inhibition of JNK and downregulation of JNK expression by RNA interference reduced the nitroflavone growth inhibitory activity and the apoptotic effect, opposite results were obtained when ERK 1/2 pathway was inhibited, and no effect was observed in the presence of a specific inhibitor of p38 MAPK. These findings demonstrate for the first time the antitumor action of 2´-nitroflavone in haematological cancer cell lines and suggest that both JNK and ERK 1/2 cascades are involved in the apoptotic response induced by 2´-nitroflavone in HL-60 cells.
Fil: Cárdenas, Mariano Gonzalo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Blank, Viviana Claudia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Marder, Nora Mariel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Roguin, Leonor Patricia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
2´.nitroflavone
leukemia cells
apoptosis
MAPK
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:11336/272538
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/272538
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cellsCárdenas, Mariano GonzaloBlank, Viviana ClaudiaMarder, Nora MarielRoguin, Leonor Patricia2´.nitroflavoneleukemia cellsapoptosisMAPKhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The cytotoxic activity of 2´-nitroflavone was evaluated in different haematological cancer cell lines and its mechanism of action was further studied in HL-60 cells. 2´-nitroflavone arrested cell cycle at G2/M phase and induced an apoptotic response characterized by an increase in the sub-G1 fraction of cells, a typical DNA ladder fragmentation, chromatin condensation and the detection of cells stained with Annexin V. Apoptosis was dependent on activation of at least caspase-8, -9 and -3. The involvement of death receptor pathway was indicated by the up-regulation of both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor (DR5). We also showed that 2´-nitroflavone increased expression levels of Bax and induced the release of cytochrome C to cytosol, suggesting the participation of the mitochondria-dependent pathway. When mitogen-activated protein kinases (MAPKs) pathways were studied, it was found that p38 and c-Jun NH2-terminal kinase (JNK) pathways were activated by 2´-nitroflavone in HL-60 cells, whereas phosphorylation levels of extracellular signal-regulated kinases (ERK) 1/2 significantly decreased. In addition, whereas both pharmacological inhibition of JNK and downregulation of JNK expression by RNA interference reduced the nitroflavone growth inhibitory activity and the apoptotic effect, opposite results were obtained when ERK 1/2 pathway was inhibited, and no effect was observed in the presence of a specific inhibitor of p38 MAPK. These findings demonstrate for the first time the antitumor action of 2´-nitroflavone in haematological cancer cell lines and suggest that both JNK and ERK 1/2 cascades are involved in the apoptotic response induced by 2´-nitroflavone in HL-60 cells.Fil: Cárdenas, Mariano Gonzalo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Blank, Viviana Claudia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marder, Nora Mariel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Roguin, Leonor Patricia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaLippincott Williams2012-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/272538Cárdenas, Mariano Gonzalo; Blank, Viviana Claudia; Marder, Nora Mariel; Roguin, Leonor Patricia; 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells; Lippincott Williams; Anticancer Drugs; 23; 8; 3-2012; 815-8260959-4973CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1097/CAD.0b013e328353f947info:eu-repo/semantics/altIdentifier/url/https://journals.lww.com/anti-cancerdrugs/abstract/2012/09000/2__nitroflavone_induces_apoptosis_and_modulates.5.aspxinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:29:22Zoai:ri.conicet.gov.ar:11336/272538instacron: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:34982025-10-15 14:29:22.55CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells
title 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells
spellingShingle 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells
Cárdenas, Mariano Gonzalo
2´.nitroflavone
leukemia cells
apoptosis
MAPK
title_short 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells
title_full 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells
title_fullStr 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells
title_full_unstemmed 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells
title_sort 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells
dc.creator.none.fl_str_mv Cárdenas, Mariano Gonzalo
Blank, Viviana Claudia
Marder, Nora Mariel
Roguin, Leonor Patricia
author Cárdenas, Mariano Gonzalo
author_facet Cárdenas, Mariano Gonzalo
Blank, Viviana Claudia
Marder, Nora Mariel
Roguin, Leonor Patricia
author_role author
author2 Blank, Viviana Claudia
Marder, Nora Mariel
Roguin, Leonor Patricia
author2_role author
author
author
dc.subject.none.fl_str_mv 2´.nitroflavone
leukemia cells
apoptosis
MAPK
topic 2´.nitroflavone
leukemia cells
apoptosis
MAPK
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The cytotoxic activity of 2´-nitroflavone was evaluated in different haematological cancer cell lines and its mechanism of action was further studied in HL-60 cells. 2´-nitroflavone arrested cell cycle at G2/M phase and induced an apoptotic response characterized by an increase in the sub-G1 fraction of cells, a typical DNA ladder fragmentation, chromatin condensation and the detection of cells stained with Annexin V. Apoptosis was dependent on activation of at least caspase-8, -9 and -3. The involvement of death receptor pathway was indicated by the up-regulation of both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor (DR5). We also showed that 2´-nitroflavone increased expression levels of Bax and induced the release of cytochrome C to cytosol, suggesting the participation of the mitochondria-dependent pathway. When mitogen-activated protein kinases (MAPKs) pathways were studied, it was found that p38 and c-Jun NH2-terminal kinase (JNK) pathways were activated by 2´-nitroflavone in HL-60 cells, whereas phosphorylation levels of extracellular signal-regulated kinases (ERK) 1/2 significantly decreased. In addition, whereas both pharmacological inhibition of JNK and downregulation of JNK expression by RNA interference reduced the nitroflavone growth inhibitory activity and the apoptotic effect, opposite results were obtained when ERK 1/2 pathway was inhibited, and no effect was observed in the presence of a specific inhibitor of p38 MAPK. These findings demonstrate for the first time the antitumor action of 2´-nitroflavone in haematological cancer cell lines and suggest that both JNK and ERK 1/2 cascades are involved in the apoptotic response induced by 2´-nitroflavone in HL-60 cells.
Fil: Cárdenas, Mariano Gonzalo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Blank, Viviana Claudia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Marder, Nora Mariel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Roguin, Leonor Patricia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description The cytotoxic activity of 2´-nitroflavone was evaluated in different haematological cancer cell lines and its mechanism of action was further studied in HL-60 cells. 2´-nitroflavone arrested cell cycle at G2/M phase and induced an apoptotic response characterized by an increase in the sub-G1 fraction of cells, a typical DNA ladder fragmentation, chromatin condensation and the detection of cells stained with Annexin V. Apoptosis was dependent on activation of at least caspase-8, -9 and -3. The involvement of death receptor pathway was indicated by the up-regulation of both tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor (DR5). We also showed that 2´-nitroflavone increased expression levels of Bax and induced the release of cytochrome C to cytosol, suggesting the participation of the mitochondria-dependent pathway. When mitogen-activated protein kinases (MAPKs) pathways were studied, it was found that p38 and c-Jun NH2-terminal kinase (JNK) pathways were activated by 2´-nitroflavone in HL-60 cells, whereas phosphorylation levels of extracellular signal-regulated kinases (ERK) 1/2 significantly decreased. In addition, whereas both pharmacological inhibition of JNK and downregulation of JNK expression by RNA interference reduced the nitroflavone growth inhibitory activity and the apoptotic effect, opposite results were obtained when ERK 1/2 pathway was inhibited, and no effect was observed in the presence of a specific inhibitor of p38 MAPK. These findings demonstrate for the first time the antitumor action of 2´-nitroflavone in haematological cancer cell lines and suggest that both JNK and ERK 1/2 cascades are involved in the apoptotic response induced by 2´-nitroflavone in HL-60 cells.
publishDate 2012
dc.date.none.fl_str_mv 2012-03
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/11336/272538
Cárdenas, Mariano Gonzalo; Blank, Viviana Claudia; Marder, Nora Mariel; Roguin, Leonor Patricia; 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells; Lippincott Williams; Anticancer Drugs; 23; 8; 3-2012; 815-826
0959-4973
CONICET Digital
CONICET
url http://hdl.handle.net/11336/272538
identifier_str_mv Cárdenas, Mariano Gonzalo; Blank, Viviana Claudia; Marder, Nora Mariel; Roguin, Leonor Patricia; 2′-Nitroflavone induces apoptosis and modulates mitogen-activated protein kinase pathways in human leukaemia cells; Lippincott Williams; Anticancer Drugs; 23; 8; 3-2012; 815-826
0959-4973
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1097/CAD.0b013e328353f947
info:eu-repo/semantics/altIdentifier/url/https://journals.lww.com/anti-cancerdrugs/abstract/2012/09000/2__nitroflavone_induces_apoptosis_and_modulates.5.aspx
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 Lippincott Williams
publisher.none.fl_str_mv Lippincott Williams
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 13.22299

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