Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells

Autores
Wempe, Stacy L.; Gamarra Luques, Carlos Diego; Telleria, Carlos Marcelo
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
We have previously shown that the antiprogestin and antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells. In this work, we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided as a consequence of the persistent activity of the PI3K/Akt survival pathway. To investigate the role of this pathway in mifepristone-induced growth inhibition, human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor, LY294002. The activation of Akt in ovarian cancer cells, as marked by its phosphorylation on Ser473, was not modified by cytostatic concentrations of mifepristone, but it was blocked upon treat¬ment with LY294002. The combination mifepristone/LY294002, but not the individual drugs, killed ovarian cancer cells via apoptosis, as attested by genomic DNA fragmentation and cleavage of caspase-3, and the concomitant downregulation of antiapoptotic proteins Bcl-2 and XIAP. From a pharmacological standpoint, when assessing cell growth inhibition using a median-dose analysis algorithm, the interaction between mifepristone and LY294002 was synergistic. The lethality caused by the combination mifepristone/LY294004 in 2-dimensional cell cultures was recapitulated in organized, 3-dimensional spheroids. This study demonstrates that mifepristone and LY294002 when used individually cause cell growth arrest; yet, when combined, they cause lethality.
Fil: Wempe, Stacy L.. The University of South Dakota. Sanford School of Medicine. Division of Basic Biomedical Sciences; Estados Unidos
Fil: Gamarra Luques, Carlos Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. The University of South Dakota. Sanford School of Medicine. Division of Basic Biomedical Sciences; Estados Unidos
Fil: Telleria, Carlos Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. The University of South Dakota. Sanford School of Medicine. Division of Basic Biomedical Sciences; Estados Unidos
Materia
Ovarian Cancer
Mifepristone
Ly294002
Sinergism
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:11336/10083
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/10083
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Synergistic lethality of mifepristone and LY294002 in ovarian cancer cellsWempe, Stacy L.Gamarra Luques, Carlos DiegoTelleria, Carlos MarceloOvarian CancerMifepristoneLy294002Sinergismhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3We have previously shown that the antiprogestin and antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells. In this work, we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided as a consequence of the persistent activity of the PI3K/Akt survival pathway. To investigate the role of this pathway in mifepristone-induced growth inhibition, human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor, LY294002. The activation of Akt in ovarian cancer cells, as marked by its phosphorylation on Ser473, was not modified by cytostatic concentrations of mifepristone, but it was blocked upon treat¬ment with LY294002. The combination mifepristone/LY294002, but not the individual drugs, killed ovarian cancer cells via apoptosis, as attested by genomic DNA fragmentation and cleavage of caspase-3, and the concomitant downregulation of antiapoptotic proteins Bcl-2 and XIAP. From a pharmacological standpoint, when assessing cell growth inhibition using a median-dose analysis algorithm, the interaction between mifepristone and LY294002 was synergistic. The lethality caused by the combination mifepristone/LY294004 in 2-dimensional cell cultures was recapitulated in organized, 3-dimensional spheroids. This study demonstrates that mifepristone and LY294002 when used individually cause cell growth arrest; yet, when combined, they cause lethality.Fil: Wempe, Stacy L.. The University of South Dakota. Sanford School of Medicine. Division of Basic Biomedical Sciences; Estados UnidosFil: Gamarra Luques, Carlos Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. The University of South Dakota. Sanford School of Medicine. Division of Basic Biomedical Sciences; Estados UnidosFil: Telleria, Carlos Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. The University of South Dakota. Sanford School of Medicine. Division of Basic Biomedical Sciences; Estados UnidosLibertas Academica2013-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/10083Wempe, Stacy L.; Gamarra Luques, Carlos Diego; Telleria, Carlos Marcelo; Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells; Libertas Academica; Cancer Growth and Metastasis; 6; 1-2013; 1-131179-0644enginfo:eu-repo/semantics/altIdentifier/url/http://www.la-press.com/synergistic-lethality-of-mifepristone-and-ly294002-in-ovarian-cancer-c-article-a3496info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.4137/CGM.S11124info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:05:30Zoai:ri.conicet.gov.ar:11336/10083instacron: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:34982025-09-03 10:05:31.158CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells
title Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells
spellingShingle Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells
Wempe, Stacy L.
Ovarian Cancer
Mifepristone
Ly294002
Sinergism
title_short Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells
title_full Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells
title_fullStr Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells
title_full_unstemmed Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells
title_sort Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells
dc.creator.none.fl_str_mv Wempe, Stacy L.
Gamarra Luques, Carlos Diego
Telleria, Carlos Marcelo
author Wempe, Stacy L.
author_facet Wempe, Stacy L.
Gamarra Luques, Carlos Diego
Telleria, Carlos Marcelo
author_role author
author2 Gamarra Luques, Carlos Diego
Telleria, Carlos Marcelo
author2_role author
author
dc.subject.none.fl_str_mv Ovarian Cancer
Mifepristone
Ly294002
Sinergism
topic Ovarian Cancer
Mifepristone
Ly294002
Sinergism
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv We have previously shown that the antiprogestin and antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells. In this work, we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided as a consequence of the persistent activity of the PI3K/Akt survival pathway. To investigate the role of this pathway in mifepristone-induced growth inhibition, human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor, LY294002. The activation of Akt in ovarian cancer cells, as marked by its phosphorylation on Ser473, was not modified by cytostatic concentrations of mifepristone, but it was blocked upon treat¬ment with LY294002. The combination mifepristone/LY294002, but not the individual drugs, killed ovarian cancer cells via apoptosis, as attested by genomic DNA fragmentation and cleavage of caspase-3, and the concomitant downregulation of antiapoptotic proteins Bcl-2 and XIAP. From a pharmacological standpoint, when assessing cell growth inhibition using a median-dose analysis algorithm, the interaction between mifepristone and LY294002 was synergistic. The lethality caused by the combination mifepristone/LY294004 in 2-dimensional cell cultures was recapitulated in organized, 3-dimensional spheroids. This study demonstrates that mifepristone and LY294002 when used individually cause cell growth arrest; yet, when combined, they cause lethality.
Fil: Wempe, Stacy L.. The University of South Dakota. Sanford School of Medicine. Division of Basic Biomedical Sciences; Estados Unidos
Fil: Gamarra Luques, Carlos Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. The University of South Dakota. Sanford School of Medicine. Division of Basic Biomedical Sciences; Estados Unidos
Fil: Telleria, Carlos Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. The University of South Dakota. Sanford School of Medicine. Division of Basic Biomedical Sciences; Estados Unidos
description We have previously shown that the antiprogestin and antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells. In this work, we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided as a consequence of the persistent activity of the PI3K/Akt survival pathway. To investigate the role of this pathway in mifepristone-induced growth inhibition, human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor, LY294002. The activation of Akt in ovarian cancer cells, as marked by its phosphorylation on Ser473, was not modified by cytostatic concentrations of mifepristone, but it was blocked upon treat¬ment with LY294002. The combination mifepristone/LY294002, but not the individual drugs, killed ovarian cancer cells via apoptosis, as attested by genomic DNA fragmentation and cleavage of caspase-3, and the concomitant downregulation of antiapoptotic proteins Bcl-2 and XIAP. From a pharmacological standpoint, when assessing cell growth inhibition using a median-dose analysis algorithm, the interaction between mifepristone and LY294002 was synergistic. The lethality caused by the combination mifepristone/LY294004 in 2-dimensional cell cultures was recapitulated in organized, 3-dimensional spheroids. This study demonstrates that mifepristone and LY294002 when used individually cause cell growth arrest; yet, when combined, they cause lethality.
publishDate 2013
dc.date.none.fl_str_mv 2013-01
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/11336/10083
Wempe, Stacy L.; Gamarra Luques, Carlos Diego; Telleria, Carlos Marcelo; Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells; Libertas Academica; Cancer Growth and Metastasis; 6; 1-2013; 1-13
1179-0644
url http://hdl.handle.net/11336/10083
identifier_str_mv Wempe, Stacy L.; Gamarra Luques, Carlos Diego; Telleria, Carlos Marcelo; Synergistic lethality of mifepristone and LY294002 in ovarian cancer cells; Libertas Academica; Cancer Growth and Metastasis; 6; 1-2013; 1-13
1179-0644
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.la-press.com/synergistic-lethality-of-mifepristone-and-ly294002-in-ovarian-cancer-c-article-a3496
info:eu-repo/semantics/altIdentifier/url/http://dx.doi.org/10.4137/CGM.S11124
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 Libertas Academica
publisher.none.fl_str_mv Libertas Academica
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
_version_ 1842269914535034880
score 13.13397

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