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Título : Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
Autor : 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 
Fecha de publicación : 2019
Editorial : Impact Journals
Cita : 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:
Resumen : 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.
ISSN : 1949-2553
Disciplina: MEDICINA
DOI: 10.18632/oncotarget.26890
Derechos: Acceso Abierto
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