Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells

Autores
Díaz Flaqué, María Celeste; Cayrol, Maria Florencia; Sterle, Helena Andrea; Aschero, María del Rosario; Díaz Albuja, Johanna Abigail; Isse, Blanca Alicia de Los Angeles G.; Farias, Ricardo Norberto; Cerchietti, Leandro; Rosemblit, Cinthia; Cremaschi, Graciela Alicia
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Thyroid hormones (THs) 3,3′,5-triiodo-L-thyronine (T3) and L-thyroxine (T4) are important regulators of the metabolism and physiology of most normal tissues.Cytochrome P450 family 3A members are drug metabolizing enzymes involved in theactivation and detoxification of several drugs. CYP3A4 is the major enzyme involvedin the metabolism of chemotherapeutic drugs. In this work, we demonstrate thatTHs induce a significant increase in CYP3A4 mRNA levels, protein expression andmetabolic activity through the membrane receptor integrin αvβ3 and the activation ofsignalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4modulation may act as an important regulator in the metabolism of doxorubicin(Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, noTH-mediated chemosensitivity to Doxo was observed. We also found that THs modulatethese functions by activating the membrane receptor integrin αvβ3. In addition, weshowed that the thyroid status can modulate CYP450 mRNA levels in tumor and livertissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxotreatment in hypothyroid mice was associated with lower tumors, displaying lowerlevels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYPenzymes were found in livers from Doxo treated hypothyroid mice respect to control.These results present a new mechanism by which TH could modulate chemotherapyresponse. These findings highlight the importance of evaluating thyroid status inpatients during application of T-cell lymphoma therapeutic regimens.
Fil: Díaz Flaqué, María Celeste. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Cayrol, Maria Florencia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Aschero, María del Rosario. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Díaz Albuja, Johanna Abigail. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Isse, Blanca Alicia de Los Angeles G.. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina
Fil: Farias, Ricardo Norberto. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cornell University; Estados Unidos
Fil: Rosemblit, Cinthia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Materia
Thyroid hormones
doxorubicin
lymphoma T
CYP3A4
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:11336/136181
Acceder
id CONICETDig_1dd44328cb79e0dccf52674eb3b24670
oai_identifier_str oai:ri.conicet.gov.ar:11336/136181
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cellsDíaz Flaqué, María CelesteCayrol, Maria FlorenciaSterle, Helena AndreaAschero, María del RosarioDíaz Albuja, Johanna AbigailIsse, Blanca Alicia de Los Angeles G.Farias, Ricardo NorbertoCerchietti, LeandroRosemblit, CinthiaCremaschi, Graciela AliciaThyroid hormonesdoxorubicinlymphoma TCYP3A4https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Thyroid hormones (THs) 3,3′,5-triiodo-L-thyronine (T3) and L-thyroxine (T4) are important regulators of the metabolism and physiology of most normal tissues.Cytochrome P450 family 3A members are drug metabolizing enzymes involved in theactivation and detoxification of several drugs. CYP3A4 is the major enzyme involvedin the metabolism of chemotherapeutic drugs. In this work, we demonstrate thatTHs induce a significant increase in CYP3A4 mRNA levels, protein expression andmetabolic activity through the membrane receptor integrin αvβ3 and the activation ofsignalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4modulation may act as an important regulator in the metabolism of doxorubicin(Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, noTH-mediated chemosensitivity to Doxo was observed. We also found that THs modulatethese functions by activating the membrane receptor integrin αvβ3. In addition, weshowed that the thyroid status can modulate CYP450 mRNA levels in tumor and livertissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxotreatment in hypothyroid mice was associated with lower tumors, displaying lowerlevels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYPenzymes were found in livers from Doxo treated hypothyroid mice respect to control.These results present a new mechanism by which TH could modulate chemotherapyresponse. These findings highlight the importance of evaluating thyroid status inpatients during application of T-cell lymphoma therapeutic regimens.Fil: Díaz Flaqué, María Celeste. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Cayrol, Maria Florencia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Aschero, María del Rosario. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Díaz Albuja, Johanna Abigail. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Isse, Blanca Alicia de Los Angeles G.. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; ArgentinaFil: Farias, Ricardo Norberto. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cornell University; Estados UnidosFil: Rosemblit, Cinthia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaFil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; ArgentinaImpact Journals2019-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/136181Díaz Flaqué, María Celeste; Cayrol, Maria Florencia; Sterle, Helena Andrea; Aschero, María del Rosario; Díaz Albuja, Johanna Abigail; et al.; Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells; Impact Journals; Oncotarget; 10; 32; 4-2019; 3051-30651949-2553CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.oncotarget.com/article/26890/text/info:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.26890info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:31:53Zoai:ri.conicet.gov.ar:11336/136181instacron: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 15:31:53.949CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
title Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
spellingShingle Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
Díaz Flaqué, María Celeste
Thyroid hormones
doxorubicin
lymphoma T
CYP3A4
title_short Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
title_full Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
title_fullStr Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
title_full_unstemmed Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
title_sort Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
dc.creator.none.fl_str_mv Díaz Flaqué, María Celeste
Cayrol, Maria Florencia
Sterle, Helena Andrea
Aschero, María del Rosario
Díaz Albuja, Johanna Abigail
Isse, Blanca Alicia de Los Angeles G.
Farias, Ricardo Norberto
Cerchietti, Leandro
Rosemblit, Cinthia
Cremaschi, Graciela Alicia
author Díaz Flaqué, María Celeste
author_facet Díaz Flaqué, María Celeste
Cayrol, Maria Florencia
Sterle, Helena Andrea
Aschero, María del Rosario
Díaz Albuja, Johanna Abigail
Isse, Blanca Alicia de Los Angeles G.
Farias, Ricardo Norberto
Cerchietti, Leandro
Rosemblit, Cinthia
Cremaschi, Graciela Alicia
author_role author
author2 Cayrol, Maria Florencia
Sterle, Helena Andrea
Aschero, María del Rosario
Díaz Albuja, Johanna Abigail
Isse, Blanca Alicia de Los Angeles G.
Farias, Ricardo Norberto
Cerchietti, Leandro
Rosemblit, Cinthia
Cremaschi, Graciela Alicia
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Thyroid hormones
doxorubicin
lymphoma T
CYP3A4
topic Thyroid hormones
doxorubicin
lymphoma T
CYP3A4
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Thyroid hormones (THs) 3,3′,5-triiodo-L-thyronine (T3) and L-thyroxine (T4) are important regulators of the metabolism and physiology of most normal tissues.Cytochrome P450 family 3A members are drug metabolizing enzymes involved in theactivation and detoxification of several drugs. CYP3A4 is the major enzyme involvedin the metabolism of chemotherapeutic drugs. In this work, we demonstrate thatTHs induce a significant increase in CYP3A4 mRNA levels, protein expression andmetabolic activity through the membrane receptor integrin αvβ3 and the activation ofsignalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4modulation may act as an important regulator in the metabolism of doxorubicin(Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, noTH-mediated chemosensitivity to Doxo was observed. We also found that THs modulatethese functions by activating the membrane receptor integrin αvβ3. In addition, weshowed that the thyroid status can modulate CYP450 mRNA levels in tumor and livertissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxotreatment in hypothyroid mice was associated with lower tumors, displaying lowerlevels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYPenzymes were found in livers from Doxo treated hypothyroid mice respect to control.These results present a new mechanism by which TH could modulate chemotherapyresponse. These findings highlight the importance of evaluating thyroid status inpatients during application of T-cell lymphoma therapeutic regimens.
Fil: Díaz Flaqué, María Celeste. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Cayrol, Maria Florencia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Aschero, María del Rosario. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Díaz Albuja, Johanna Abigail. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Isse, Blanca Alicia de Los Angeles G.. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina
Fil: Farias, Ricardo Norberto. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cerchietti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Cornell University; Estados Unidos
Fil: Rosemblit, Cinthia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
Fil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina
description Thyroid hormones (THs) 3,3′,5-triiodo-L-thyronine (T3) and L-thyroxine (T4) are important regulators of the metabolism and physiology of most normal tissues.Cytochrome P450 family 3A members are drug metabolizing enzymes involved in theactivation and detoxification of several drugs. CYP3A4 is the major enzyme involvedin the metabolism of chemotherapeutic drugs. In this work, we demonstrate thatTHs induce a significant increase in CYP3A4 mRNA levels, protein expression andmetabolic activity through the membrane receptor integrin αvβ3 and the activation ofsignalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4modulation may act as an important regulator in the metabolism of doxorubicin(Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, noTH-mediated chemosensitivity to Doxo was observed. We also found that THs modulatethese functions by activating the membrane receptor integrin αvβ3. In addition, weshowed that the thyroid status can modulate CYP450 mRNA levels in tumor and livertissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxotreatment in hypothyroid mice was associated with lower tumors, displaying lowerlevels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYPenzymes were found in livers from Doxo treated hypothyroid mice respect to control.These results present a new mechanism by which TH could modulate chemotherapyresponse. These findings highlight the importance of evaluating thyroid status inpatients during application of T-cell lymphoma therapeutic regimens.
publishDate 2019
dc.date.none.fl_str_mv 2019-04
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/11336/136181
Díaz Flaqué, María Celeste; Cayrol, Maria Florencia; Sterle, Helena Andrea; Aschero, María del Rosario; Díaz Albuja, Johanna Abigail; et al.; Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells; Impact Journals; Oncotarget; 10; 32; 4-2019; 3051-3065
1949-2553
CONICET Digital
CONICET
url http://hdl.handle.net/11336/136181
identifier_str_mv Díaz Flaqué, María Celeste; Cayrol, Maria Florencia; Sterle, Helena Andrea; Aschero, María del Rosario; Díaz Albuja, Johanna Abigail; et al.; Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells; Impact Journals; Oncotarget; 10; 32; 4-2019; 3051-3065
1949-2553
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.oncotarget.com/article/26890/text/
info:eu-repo/semantics/altIdentifier/doi/10.18632/oncotarget.26890
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
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
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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