Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels

Autores
Reinicke, Kathryn E.; Bey, Erik A.; Bentle, Melissa S.; Pink, John J.; Ingalls, Stephen T.; Hoppel, Charles L.; Misico, Rosana Isabel; Arzac, Gisella M.; Burton, Gerardo; Bornmann, William G.; Sutton, Damon; Gao, Jinming; Boothman, David A.
Año de publicación
2005
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
β-Lapachone, an o-naphthoquinone, induces a novel caspase- and p53-independent apoptotic pathway dependent on NAD (P) H:quinone oxidoreductase 1 (NQO1). NQO1 reduces β-lapachone to an unstable hydroquinone that rapidly undergoes a two-step oxidation back to the parent compound, perpetuating a futile redox cycle. A deficiency or inhibition of NQO1 rendered cells resistant to beta;-lapachone. Thus, β-lapachone has great potential for the treatment of specific cancers with elevated NQO1 levels (e.g., breast, non - small cell lung, pancreatic, colon, and prostate cancers). We report the development of mono(arylimino) derivatives of β-lapachone as potential prodrugs. These derivatives are relatively nontoxic and not substrates for NQO1 when initially diluted in water. In solution, however, they undergo hydrolytic conversion to β-lapachone at rates dependent on the electron-withdrawing strength of their substituent groups and pH of the diluent. NQO1 enzyme assays, UV-visible spectrophotometry, high-performance liquid chromatography-electrospray ionization-mass spectrometry, and nuclear magnetic resonance analyses confirmed and monitored conversion of each derivative to β-lapachone. Once converted, β-lapachone derivatives caused NQO1-dependent, μ-calpain-mediated cell death in human cancer cells identical to that caused by β-lapachone. Interestingly, coadministration of N-acetyt-L-cysteine prevented derivative-induced cytotoxicity but did not affect β-lapachone lethality. Nuclear magnetic resonance analyses indicated that prevention of β-lapachone derivative cytotoxicity was the result of direct modification of these derivatives by N-acetyl-L-cysteine, preventing their conversion to β-lapachone. The use of β-lapachone mono(arylimino) prodrug derivatives, or more specifically a derivative converted in a tumor-specific manner (i.e., in the acidic local environment of the tumor tissue), should reduce normal tissue toxicity while eliciting tumor-selective cell killing by NQO1 bioactivation.
Fil: Reinicke, Kathryn E.. Case Western Reserve University; Estados Unidos
Fil: Bey, Erik A.. Case Western Reserve University; Estados Unidos
Fil: Bentle, Melissa S.. Case Western Reserve University; Estados Unidos
Fil: Pink, John J.. Case Western Reserve University; Estados Unidos
Fil: Ingalls, Stephen T.. Case Western Reserve University; Estados Unidos
Fil: Hoppel, Charles L.. Case Western Reserve University; Estados Unidos
Fil: Misico, Rosana Isabel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
Fil: Arzac, Gisella M.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Burton, Gerardo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
Fil: Bornmann, William G.. M.D. Anderson University; Estados Unidos
Fil: Sutton, Damon. Case Western Reserve University; Estados Unidos
Fil: Gao, Jinming. Case Western Reserve University; Estados Unidos
Fil: Boothman, David A.. Case Western Reserve University; Estados Unidos
Materia
B-LAPACHONE DERIVATIVES
APOPTOSIS
BREAST CANCER
NQO1 (DT-diaphorase)
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:11336/88169
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/88169
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levelsReinicke, Kathryn E.Bey, Erik A.Bentle, Melissa S.Pink, John J.Ingalls, Stephen T.Hoppel, Charles L.Misico, Rosana IsabelArzac, Gisella M.Burton, GerardoBornmann, William G.Sutton, DamonGao, JinmingBoothman, David A.B-LAPACHONE DERIVATIVESAPOPTOSISBREAST CANCERNQO1 (DT-diaphorase)https://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1β-Lapachone, an o-naphthoquinone, induces a novel caspase- and p53-independent apoptotic pathway dependent on NAD (P) H:quinone oxidoreductase 1 (NQO1). NQO1 reduces β-lapachone to an unstable hydroquinone that rapidly undergoes a two-step oxidation back to the parent compound, perpetuating a futile redox cycle. A deficiency or inhibition of NQO1 rendered cells resistant to beta;-lapachone. Thus, β-lapachone has great potential for the treatment of specific cancers with elevated NQO1 levels (e.g., breast, non - small cell lung, pancreatic, colon, and prostate cancers). We report the development of mono(arylimino) derivatives of β-lapachone as potential prodrugs. These derivatives are relatively nontoxic and not substrates for NQO1 when initially diluted in water. In solution, however, they undergo hydrolytic conversion to β-lapachone at rates dependent on the electron-withdrawing strength of their substituent groups and pH of the diluent. NQO1 enzyme assays, UV-visible spectrophotometry, high-performance liquid chromatography-electrospray ionization-mass spectrometry, and nuclear magnetic resonance analyses confirmed and monitored conversion of each derivative to β-lapachone. Once converted, β-lapachone derivatives caused NQO1-dependent, μ-calpain-mediated cell death in human cancer cells identical to that caused by β-lapachone. Interestingly, coadministration of N-acetyt-L-cysteine prevented derivative-induced cytotoxicity but did not affect β-lapachone lethality. Nuclear magnetic resonance analyses indicated that prevention of β-lapachone derivative cytotoxicity was the result of direct modification of these derivatives by N-acetyl-L-cysteine, preventing their conversion to β-lapachone. The use of β-lapachone mono(arylimino) prodrug derivatives, or more specifically a derivative converted in a tumor-specific manner (i.e., in the acidic local environment of the tumor tissue), should reduce normal tissue toxicity while eliciting tumor-selective cell killing by NQO1 bioactivation.Fil: Reinicke, Kathryn E.. Case Western Reserve University; Estados UnidosFil: Bey, Erik A.. Case Western Reserve University; Estados UnidosFil: Bentle, Melissa S.. Case Western Reserve University; Estados UnidosFil: Pink, John J.. Case Western Reserve University; Estados UnidosFil: Ingalls, Stephen T.. Case Western Reserve University; Estados UnidosFil: Hoppel, Charles L.. Case Western Reserve University; Estados UnidosFil: Misico, Rosana Isabel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; ArgentinaFil: Arzac, Gisella M.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Burton, Gerardo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; ArgentinaFil: Bornmann, William G.. M.D. Anderson University; Estados UnidosFil: Sutton, Damon. Case Western Reserve University; Estados UnidosFil: Gao, Jinming. Case Western Reserve University; Estados UnidosFil: Boothman, David A.. Case Western Reserve University; Estados UnidosAmerican Association for Cancer Research2005-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/88169Reinicke, Kathryn E.; Bey, Erik A.; Bentle, Melissa S.; Pink, John J.; Ingalls, Stephen T.; et al.; Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels; American Association for Cancer Research; Clinical Cancer Research; 11; 8; 4-2005; 3055-30641078-0432CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/content/11/8/3055info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-04-2185info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:12:25Zoai:ri.conicet.gov.ar:11336/88169instacron: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 15:12:26.115CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
title Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
spellingShingle Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
Reinicke, Kathryn E.
B-LAPACHONE DERIVATIVES
APOPTOSIS
BREAST CANCER
NQO1 (DT-diaphorase)
title_short Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
title_full Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
title_fullStr Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
title_full_unstemmed Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
title_sort Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels
dc.creator.none.fl_str_mv Reinicke, Kathryn E.
Bey, Erik A.
Bentle, Melissa S.
Pink, John J.
Ingalls, Stephen T.
Hoppel, Charles L.
Misico, Rosana Isabel
Arzac, Gisella M.
Burton, Gerardo
Bornmann, William G.
Sutton, Damon
Gao, Jinming
Boothman, David A.
author Reinicke, Kathryn E.
author_facet Reinicke, Kathryn E.
Bey, Erik A.
Bentle, Melissa S.
Pink, John J.
Ingalls, Stephen T.
Hoppel, Charles L.
Misico, Rosana Isabel
Arzac, Gisella M.
Burton, Gerardo
Bornmann, William G.
Sutton, Damon
Gao, Jinming
Boothman, David A.
author_role author
author2 Bey, Erik A.
Bentle, Melissa S.
Pink, John J.
Ingalls, Stephen T.
Hoppel, Charles L.
Misico, Rosana Isabel
Arzac, Gisella M.
Burton, Gerardo
Bornmann, William G.
Sutton, Damon
Gao, Jinming
Boothman, David A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv B-LAPACHONE DERIVATIVES
APOPTOSIS
BREAST CANCER
NQO1 (DT-diaphorase)
topic B-LAPACHONE DERIVATIVES
APOPTOSIS
BREAST CANCER
NQO1 (DT-diaphorase)
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv β-Lapachone, an o-naphthoquinone, induces a novel caspase- and p53-independent apoptotic pathway dependent on NAD (P) H:quinone oxidoreductase 1 (NQO1). NQO1 reduces β-lapachone to an unstable hydroquinone that rapidly undergoes a two-step oxidation back to the parent compound, perpetuating a futile redox cycle. A deficiency or inhibition of NQO1 rendered cells resistant to beta;-lapachone. Thus, β-lapachone has great potential for the treatment of specific cancers with elevated NQO1 levels (e.g., breast, non - small cell lung, pancreatic, colon, and prostate cancers). We report the development of mono(arylimino) derivatives of β-lapachone as potential prodrugs. These derivatives are relatively nontoxic and not substrates for NQO1 when initially diluted in water. In solution, however, they undergo hydrolytic conversion to β-lapachone at rates dependent on the electron-withdrawing strength of their substituent groups and pH of the diluent. NQO1 enzyme assays, UV-visible spectrophotometry, high-performance liquid chromatography-electrospray ionization-mass spectrometry, and nuclear magnetic resonance analyses confirmed and monitored conversion of each derivative to β-lapachone. Once converted, β-lapachone derivatives caused NQO1-dependent, μ-calpain-mediated cell death in human cancer cells identical to that caused by β-lapachone. Interestingly, coadministration of N-acetyt-L-cysteine prevented derivative-induced cytotoxicity but did not affect β-lapachone lethality. Nuclear magnetic resonance analyses indicated that prevention of β-lapachone derivative cytotoxicity was the result of direct modification of these derivatives by N-acetyl-L-cysteine, preventing their conversion to β-lapachone. The use of β-lapachone mono(arylimino) prodrug derivatives, or more specifically a derivative converted in a tumor-specific manner (i.e., in the acidic local environment of the tumor tissue), should reduce normal tissue toxicity while eliciting tumor-selective cell killing by NQO1 bioactivation.
Fil: Reinicke, Kathryn E.. Case Western Reserve University; Estados Unidos
Fil: Bey, Erik A.. Case Western Reserve University; Estados Unidos
Fil: Bentle, Melissa S.. Case Western Reserve University; Estados Unidos
Fil: Pink, John J.. Case Western Reserve University; Estados Unidos
Fil: Ingalls, Stephen T.. Case Western Reserve University; Estados Unidos
Fil: Hoppel, Charles L.. Case Western Reserve University; Estados Unidos
Fil: Misico, Rosana Isabel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
Fil: Arzac, Gisella M.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina
Fil: Burton, Gerardo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina
Fil: Bornmann, William G.. M.D. Anderson University; Estados Unidos
Fil: Sutton, Damon. Case Western Reserve University; Estados Unidos
Fil: Gao, Jinming. Case Western Reserve University; Estados Unidos
Fil: Boothman, David A.. Case Western Reserve University; Estados Unidos
description β-Lapachone, an o-naphthoquinone, induces a novel caspase- and p53-independent apoptotic pathway dependent on NAD (P) H:quinone oxidoreductase 1 (NQO1). NQO1 reduces β-lapachone to an unstable hydroquinone that rapidly undergoes a two-step oxidation back to the parent compound, perpetuating a futile redox cycle. A deficiency or inhibition of NQO1 rendered cells resistant to beta;-lapachone. Thus, β-lapachone has great potential for the treatment of specific cancers with elevated NQO1 levels (e.g., breast, non - small cell lung, pancreatic, colon, and prostate cancers). We report the development of mono(arylimino) derivatives of β-lapachone as potential prodrugs. These derivatives are relatively nontoxic and not substrates for NQO1 when initially diluted in water. In solution, however, they undergo hydrolytic conversion to β-lapachone at rates dependent on the electron-withdrawing strength of their substituent groups and pH of the diluent. NQO1 enzyme assays, UV-visible spectrophotometry, high-performance liquid chromatography-electrospray ionization-mass spectrometry, and nuclear magnetic resonance analyses confirmed and monitored conversion of each derivative to β-lapachone. Once converted, β-lapachone derivatives caused NQO1-dependent, μ-calpain-mediated cell death in human cancer cells identical to that caused by β-lapachone. Interestingly, coadministration of N-acetyt-L-cysteine prevented derivative-induced cytotoxicity but did not affect β-lapachone lethality. Nuclear magnetic resonance analyses indicated that prevention of β-lapachone derivative cytotoxicity was the result of direct modification of these derivatives by N-acetyl-L-cysteine, preventing their conversion to β-lapachone. The use of β-lapachone mono(arylimino) prodrug derivatives, or more specifically a derivative converted in a tumor-specific manner (i.e., in the acidic local environment of the tumor tissue), should reduce normal tissue toxicity while eliciting tumor-selective cell killing by NQO1 bioactivation.
publishDate 2005
dc.date.none.fl_str_mv 2005-04
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/11336/88169
Reinicke, Kathryn E.; Bey, Erik A.; Bentle, Melissa S.; Pink, John J.; Ingalls, Stephen T.; et al.; Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels; American Association for Cancer Research; Clinical Cancer Research; 11; 8; 4-2005; 3055-3064
1078-0432
CONICET Digital
CONICET
url http://hdl.handle.net/11336/88169
identifier_str_mv Reinicke, Kathryn E.; Bey, Erik A.; Bentle, Melissa S.; Pink, John J.; Ingalls, Stephen T.; et al.; Development of β-Lapachone prodrugs for therapy against human cancer cells with elevated NAD(P)H:quinone oxidoreductase 1 levels; American Association for Cancer Research; Clinical Cancer Research; 11; 8; 4-2005; 3055-3064
1078-0432
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://clincancerres.aacrjournals.org/content/11/8/3055
info:eu-repo/semantics/altIdentifier/doi/10.1158/1078-0432.CCR-04-2185
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
application/pdf
dc.publisher.none.fl_str_mv American Association for Cancer Research
publisher.none.fl_str_mv American Association for Cancer Research
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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