Thyroid hormones induce doxorubicin chemosensitivity through enzymes involved in chemotherapy metabolism in lymphoma T cells
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María Celeste Díaz Flaqué1, Maria Florencia Cayrol1, Helena Andrea Sterle1, María del Rosario Aschero1, Johanna Abigail Díaz Albuja1, Blanca Isse2, Ricardo Norberto Farías2, Leandro Cerchietti3, Cinthia Rosemblit1 and Graciela Alicia Cremaschi1
1 Instituto de Investigaciones Biomédicas (BIOMED), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina (UCA), Buenos Aires, Argentina
2 Departmento de Bioquimica Nutricional, CONICET, Universidad Nacional de Tucuman, Instituto de Quimica Biologica “Dr Bernabe Bloj”, San Miguel de Tucuman, Tucuman, Argentina
3 Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY, USA
|Graciela Alicia Cremaschi,||email:||
Keywords: thyroid hormones; CYP 450; integrin αvβ3; doxorubicin; T-cell lymphoma
Received: November 03, 2018 Accepted: March 23, 2019 Published: April 30, 2019
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.
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