Thyroid hormones induces chemosensitivity to doxorubicin in Jurkat cells througth the modulation of enzymes involved in chemotherapy drug metabolism.

DÍAZ FLAQUÉ, M.C.; CAYROL, M.F.; STERLE, H.; ROSEMBLIT, C.; PAULAZO, M.A.; DÍAZ ALBUJA, J.; KLECHA, A. ; BARREIRO ARCOS, M.L.; CREMASCHI, G.

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Investigación Clínica (SAIC) en conjunto con Sociedades de Biociencias

Thyroid hormones (TH)- triiodothyronine (T3) and Thyroxine (T4)- ares important regulators od the metabolism and physiology of most normal tissues. We recently showed that TH stimulate the proliferation and metabolismo f T cells. To assess the effect of TH on the response to conventional chemotherapy, we determined the doxorubicin (DOX) dose that inhibits proliferation by 50 % (IC50) in presence or absence of TH. As expected, DOX induces cytotoxicity in a dose-dependent manner in cells treated or not with TH. It is important to note that under proliferative conditions, pretreatment with TH sensitizes Jurkat cells to DOX treatment. Noteworthy pretreatment with TH significantly decreases chemosensitivity to DOX by 50 % (p≤0.01). It is well known that CYP3A4 is the major enzyme involved in the metabolismo f chemotherapeutic drugs. We have previously demostrated that HT induce a significant increase of CYP 3A4 mRNA synthesis, protein expression and metabolic activity through both the canonical (TR) and membrane (integrin αVβ3) receptors. We reasoned that TH-induced CYP3A4 modulation may act as an important regulator in the metabolisms of DOX. To further explored the role of CYP3A4 in TH-chemosensitivity to DOX we used siRNA knock down of CYP3A4 in Jurkat cells. As expected, in CYP3A4 knocked down cells, no TH-mediated chemosensitivity was observed.We also found that TH modulate these functions by activating the membrane receptor integrin αVβ3. We found that inactivation of integrin αVβ3 by either a chemical inhibitor or siRNA inhibit TH-induced DOX chemosensitivity. 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.