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Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508960/ https://www.ncbi.nlm.nih.gov/pubmed/31105885 http://dx.doi.org/10.18632/oncotarget.26890 |
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author | Díaz Flaqué, María Celeste Cayrol, Maria Florencia Sterle, Helena Andrea del Rosario Aschero, María Díaz Albuja, Johanna Abigail Isse, Blanca Farías, Ricardo Norberto Cerchietti, Leandro Rosemblit, Cinthia Cremaschi, Graciela Alicia |
author_facet | Díaz Flaqué, María Celeste Cayrol, Maria Florencia Sterle, Helena Andrea del Rosario Aschero, María Díaz Albuja, Johanna Abigail Isse, Blanca Farías, Ricardo Norberto Cerchietti, Leandro Rosemblit, Cinthia Cremaschi, Graciela Alicia |
author_sort | Díaz Flaqué, María Celeste |
collection | PubMed |
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 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. |
format | Online Article Text |
id | pubmed-6508960 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-65089602019-05-17 Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells Díaz Flaqué, María Celeste Cayrol, Maria Florencia Sterle, Helena Andrea del Rosario Aschero, María Díaz Albuja, Johanna Abigail Isse, Blanca Farías, Ricardo Norberto Cerchietti, Leandro Rosemblit, Cinthia Cremaschi, Graciela Alicia Oncotarget Research Paper 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 Journals LLC 2019-04-30 /pmc/articles/PMC6508960/ /pubmed/31105885 http://dx.doi.org/10.18632/oncotarget.26890 Text en Copyright: © 2019 Díaz Flaqué et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Díaz Flaqué, María Celeste Cayrol, Maria Florencia Sterle, Helena Andrea del Rosario Aschero, María Díaz Albuja, Johanna Abigail Isse, Blanca Farías, Ricardo Norberto Cerchietti, Leandro Rosemblit, Cinthia Cremaschi, Graciela Alicia 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 |
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_short | 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 |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508960/ https://www.ncbi.nlm.nih.gov/pubmed/31105885 http://dx.doi.org/10.18632/oncotarget.26890 |
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