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

Autores: Díaz Flaqué, María Celeste; Cayrol, María Florencia; Sterle, Helena Andrea; Aschero, María del Rosario; Díaz Albuja, Johanna Abigail; Isse, Blanca; Farías, Ricardo Norberto; Cerchietti, Leandro; Rosemblit, Cinthia; Cremaschi, Graciela Alicia
Año de publicación: 2019
Idioma: inglés
Tipo de recurso: artículo
Estado: versión publicada
Descripción: Fil: Díaz Flaqué, María Celeste. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cayrol, María Florencia. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Cayrol, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Sterle, Helena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Aschero, María Del Rosario. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Aschero, María Del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Díaz Albuja, Johanna Abigail. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Díaz Albuja, Johanna Abigail. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Isse, Blanca. Universidad Nacional de Tucumán. Instituto de Química Biológica Dr Bernabé Bloj. Departmento de Bioquimica Nutricional; Argentina
Fil: Isse, Blanca. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Farías, Ricardo Norberto. Universidad Nacional de Tucumán. Instituto de Química Biológica Dr Bernabé Bloj. Departmento de Bioquimica Nutricional; Argentina
Fil: Farías, Ricardo Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cerchietti, Leandro. Cornell University. Weill Cornell Medical College. Department of Medicine. Division of Hematology and Oncology; Estados Unidos
Fil: Rosemblit, Cinthia. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Rosemblit, Cinthia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cremaschi, Graciela A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Cremaschi, Graciela A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Abstract: 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 the activation and detoxification of several drugs. CYP3A4 is the major enzyme involved in the metabolism of chemotherapeutic drugs. In this work, we demonstrate that THs induce a significant increase in CYP3A4 mRNA levels, protein expression and metabolic activity through the membrane receptor integrin αvβ3 and the activation of signalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4 modulation may act as an important regulator in the metabolism of doxorubicin (Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, no TH-mediated chemosensitivity to Doxo was observed. We also found that THs modulate these functions by activating the membrane receptor integrin αvβ3. In addition, we showed that the thyroid status can modulate CYP450 mRNA levels in tumor and liver tissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxo treatment in hypothyroid mice was associated with lower tumors, displaying lower levels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYP enzymes were found in livers from Doxo treated hypothyroid mice respect to control. These results present a new mechanism by which TH could modulate chemotherapy response. These findings highlight the importance of evaluating thyroid status in patients during application of T-cell lymphoma therapeutic regimens.
Fuente: Oncotarget. 2019;10(32):3051-3065
Materia: GLANDULA TIROIDES
HORMONAS
METABOLISMO
QUIMIOTERAPIA
Nivel de accesibilidad: acceso abierto
Condiciones de uso: https://creativecommons.org/licenses/by-nc-sa/4.0/
Repositorio
Institución: Pontificia Universidad Católica Argentina
OAI Identificador: oai:ucacris:123456789/8674

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oai_identifier_str	oai:ucacris:123456789/8674
network_acronym_str	RIUCA
repository_id_str	2585
network_name_str	Repositorio Institucional (UCA)
spelling	Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cellsDíaz Flaqué, María CelesteCayrol, María FlorenciaSterle, Helena AndreaAschero, María del RosarioDíaz Albuja, Johanna AbigailIsse, BlancaFarías, Ricardo NorbertoCerchietti, LeandroRosemblit, CinthiaCremaschi, Graciela AliciaGLANDULA TIROIDESHORMONASMETABOLISMOQUIMIOTERAPIAFil: Díaz Flaqué, María Celeste. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cayrol, María Florencia. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Cayrol, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Sterle, Helena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aschero, María Del Rosario. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Aschero, María Del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Díaz Albuja, Johanna Abigail. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Díaz Albuja, Johanna Abigail. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Isse, Blanca. Universidad Nacional de Tucumán. Instituto de Química Biológica Dr Bernabé Bloj. Departmento de Bioquimica Nutricional; ArgentinaFil: Isse, Blanca. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Farías, Ricardo Norberto. Universidad Nacional de Tucumán. Instituto de Química Biológica Dr Bernabé Bloj. Departmento de Bioquimica Nutricional; ArgentinaFil: Farías, Ricardo Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cerchietti, Leandro. Cornell University. Weill Cornell Medical College. Department of Medicine. Division of Hematology and Oncology; Estados UnidosFil: Rosemblit, Cinthia. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Rosemblit, Cinthia. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cremaschi, Graciela A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Cremaschi, Graciela A. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaAbstract: 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 the activation and detoxification of several drugs. CYP3A4 is the major enzyme involved in the metabolism of chemotherapeutic drugs. In this work, we demonstrate that THs induce a significant increase in CYP3A4 mRNA levels, protein expression and metabolic activity through the membrane receptor integrin αvβ3 and the activation of signalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4 modulation may act as an important regulator in the metabolism of doxorubicin (Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, no TH-mediated chemosensitivity to Doxo was observed. We also found that THs modulate these functions by activating the membrane receptor integrin αvβ3. In addition, we showed that the thyroid status can modulate CYP450 mRNA levels in tumor and liver tissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxo treatment in hypothyroid mice was associated with lower tumors, displaying lower levels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYP enzymes were found in livers from Doxo treated hypothyroid mice respect to control. These results present a new mechanism by which TH could modulate chemotherapy response. These findings highlight the importance of evaluating thyroid status in patients during application of T-cell lymphoma therapeutic regimens.Impact Journals2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttps://repositorio.uca.edu.ar/handle/123456789/86741949-255310.18632/oncotarget.2689031105885Flaqué MCD, Cayrol MF, Sterle HA, et al. Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells [en línea]. Oncotarget. 2019;10(32):3051-3065. doi:10.18632/oncotarget.26890 Disponible en: https://repositorio.uca.edu.ar/handle/123456789/8674Oncotarget. 2019;10(32):3051-3065reponame:Repositorio Institucional (UCA)instname:Pontificia Universidad Católica Argentinaenginfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/4.0/2025-07-03T10:56:54Zoai:ucacris:123456789/8674instacron:UCAInstitucionalhttps://repositorio.uca.edu.ar/Universidad privadaNo correspondehttps://repositorio.uca.edu.ar/oaiclaudia_fernandez@uca.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:25852025-07-03 10:56:54.975Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentinafalse
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 GLANDULA TIROIDES HORMONAS METABOLISMO QUIMIOTERAPIA
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, María Florencia Sterle, Helena Andrea Aschero, María del Rosario Díaz Albuja, Johanna Abigail Isse, Blanca Farías, Ricardo Norberto Cerchietti, Leandro Rosemblit, Cinthia Cremaschi, Graciela Alicia
author	Díaz Flaqué, María Celeste
author_facet	Díaz Flaqué, María Celeste Cayrol, María Florencia Sterle, Helena Andrea Aschero, María del Rosario Díaz Albuja, Johanna Abigail Isse, Blanca Farías, Ricardo Norberto Cerchietti, Leandro Rosemblit, Cinthia Cremaschi, Graciela Alicia
author_role	author
author2	Cayrol, María Florencia Sterle, Helena Andrea Aschero, María del Rosario Díaz Albuja, Johanna Abigail Isse, Blanca Farías, 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	GLANDULA TIROIDES HORMONAS METABOLISMO QUIMIOTERAPIA
topic	GLANDULA TIROIDES HORMONAS METABOLISMO QUIMIOTERAPIA
dc.description.none.fl_txt_mv	Fil: Díaz Flaqué, María Celeste. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cayrol, María Florencia. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Cayrol, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Sterle, Helena Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Aschero, María Del Rosario. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Aschero, María Del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Díaz Albuja, Johanna Abigail. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Díaz Albuja, Johanna Abigail. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Isse, Blanca. Universidad Nacional de Tucumán. Instituto de Química Biológica Dr Bernabé Bloj. Departmento de Bioquimica Nutricional; Argentina Fil: Isse, Blanca. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Farías, Ricardo Norberto. Universidad Nacional de Tucumán. Instituto de Química Biológica Dr Bernabé Bloj. Departmento de Bioquimica Nutricional; Argentina Fil: Farías, Ricardo Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cerchietti, Leandro. Cornell University. Weill Cornell Medical College. Department of Medicine. Division of Hematology and Oncology; Estados Unidos Fil: Rosemblit, Cinthia. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Rosemblit, Cinthia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cremaschi, Graciela A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Cremaschi, Graciela A. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Abstract: 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 the activation and detoxification of several drugs. CYP3A4 is the major enzyme involved in the metabolism of chemotherapeutic drugs. In this work, we demonstrate that THs induce a significant increase in CYP3A4 mRNA levels, protein expression and metabolic activity through the membrane receptor integrin αvβ3 and the activation of signalling pathways through Stat1 and NF-κB. We reasoned that TH-induced CYP3A4 modulation may act as an important regulator in the metabolism of doxorubicin (Doxo). Experiments in vitro demonstrated that in CYP3A4-knocked down cells, no TH-mediated chemosensitivity to Doxo was observed. We also found that THs modulate these functions by activating the membrane receptor integrin αvβ3. In addition, we showed that the thyroid status can modulate CYP450 mRNA levels in tumor and liver tissues, and the tumor volume in response to chemotherapy in vivo. In fact, Doxo treatment in hypothyroid mice was associated with lower tumors, displaying lower levels of CYP enzymes, than euthyroid mice. However, higher mRNA levels of CYP enzymes were found in livers from Doxo treated hypothyroid mice respect to control. These results present a new mechanism by which TH could modulate chemotherapy response. These findings highlight the importance of evaluating thyroid status in patients during application of T-cell lymphoma therapeutic regimens.
description	Fil: Díaz Flaqué, María Celeste. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
publishDate	2019
dc.date.none.fl_str_mv	2019
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	https://repositorio.uca.edu.ar/handle/123456789/8674 1949-2553 10.18632/oncotarget.26890 31105885 Flaqué MCD, Cayrol MF, Sterle HA, et al. Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells [en línea]. Oncotarget. 2019;10(32):3051-3065. doi:10.18632/oncotarget.26890 Disponible en: https://repositorio.uca.edu.ar/handle/123456789/8674
url	https://repositorio.uca.edu.ar/handle/123456789/8674
identifier_str_mv	1949-2553 10.18632/oncotarget.26890 31105885 Flaqué MCD, Cayrol MF, Sterle HA, et al. Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells [en línea]. Oncotarget. 2019;10(32):3051-3065. doi:10.18632/oncotarget.26890 Disponible en: https://repositorio.uca.edu.ar/handle/123456789/8674
dc.language.none.fl_str_mv	eng
language	eng
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv	openAccess
rights_invalid_str_mv	https://creativecommons.org/licenses/by-nc-sa/4.0/
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Impact Journals
publisher.none.fl_str_mv	Impact Journals
dc.source.none.fl_str_mv	Oncotarget. 2019;10(32):3051-3065 reponame:Repositorio Institucional (UCA) instname:Pontificia Universidad Católica Argentina
reponame_str	Repositorio Institucional (UCA)
collection	Repositorio Institucional (UCA)
instname_str	Pontificia Universidad Católica Argentina
repository.name.fl_str_mv	Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentina
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Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells

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