RESUMEN
Nucleoside transporters (NTs) are essential for the uptake of therapeutic nucleoside analogs, broadly used in cancer treatment. The mechanisms responsible for NT regulation are largely unknown. IL-4 is a pro-survival signal for chronic lymphocytic leukemia (CLL) cells and has been shown to confer resistance to nucleoside analogs. The aim of this study was to investigate whether IL-4 is able to modulate the expression and function of the human equilibrative NT1 (hENT1) in primary cultures of CLL cells and, consequently, to affect cytotoxicity induced by therapeutic nucleosides analogs. We found that treatment with IL-4 (20 ng/ml for 24 h) increased mRNA hENT1 expression in CLL cells without affecting that of normal B cells. Given that the enhanced mRNA levels of hENT1 in CLL cells did not result in increased transport activity, we examined the possibility that hENT1 induced by IL-4 may require post-translational modifications to become active. We found that the acute stimulation of PKC in IL-4-treated CLL cells by short-term incubation with PMA significantly increased hENT1 transport activity and favoured fludarabine-induced apoptosis. By contrast, and in line with previous reports, IL-4 plus PMA protected CLL cells from a variety of cytotoxic agents. Our findings indicate that the combined treatment with IL-4 and PMA enhances hENT1 activity and specifically sensitizes CLL cells to undergo apoptosis induced by fludarabine.
Asunto(s)
Apoptosis/efectos de los fármacos , Linfocitos B , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Interleucina-4/farmacología , Leucemia Linfocítica Crónica de Células B , Acetato de Tetradecanoilforbol/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Linfocitos B/patología , Línea Celular Tumoral , Humanos , Interleucina-4/fisiología , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Vidarabina/análogos & derivados , Vidarabina/farmacocinética , Vidarabina/farmacologíaRESUMEN
Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. After diagnosis, patients with AML are mainly treated with standard induction chemotherapy combining cytarabine (araC) and anthracyclines. The majority of them achieve complete remission (CR) (65-80%). However, prospects for long-term survival are poor for the majority of patients. Resistance to chemotherapy therefore remains a major obstacle in the effective treatment of patients with AML. In this review, we highlight the current knowledge of substrate cycles involved in normal deoxynucleoside triphosphate (dNTPs) metabolism and their possible role in drug resistance to araC.