Paper dels transportadors de nucleòsids equilibratius en la sensibilitat a fàrmacs antineoplàsics

Resumo

ROLE OF EQUILIBRATIVE NUCLEOSIDE TRANSPORTERS IN SENSITIVITY TO ANTINEOPLASIC DRUGS Nucleoside-derivatives are currently used in the treatment of tumours and hematological malignancies. Although intracellular events involved in the pharmacological action of these compounds have been extensively studied, the role of plasma membrane transporters in nucleoside-derived drug bioavailability and action in cancer cells has not been comprehensively addressed. We examined the expression patterns and activity of nucleoside transporters in chronic lymphocytic leukaemia (CLL) patients and correlated them with in vitro fludarabine cytotoxicity. Among the known plasma membrane transporters, we observed a significant correlation between fludarabine uptake via ENT carriers and ex vivo sensitivity of CLL cells to fludarabine. Moreover, western blot results suggested a role of hENT2 in fludarabine responsiveness in CLL patients. A similar study was performed using mantle cell lymphoma (MCL) cells. In this case we found a significant correlation between protein and mRNA levels of hENT1, drug uptake and sensitivity to gemcitabine. Finally, we addressed the question of whether equilibrative nucleoside transporters contribute to the transcriptomic response associated with nucleoside-derived drug therapy. For this reason, we used a pharmacogenomic approach to determine which are the intracellular targets of 5'-DFUR action in breast cancer cell line MCF7 and how inhibition of hENT1 function contributes to the transcriptomic response. The study identified selected gene targets of 5'-DFUR action in a breast cancer cell model, and highlighted the relevant role hENT1-mediated drug uptake plays in drug action. Therefore, the results obtained further support that equilibrative nucleoside transporters are implicated in the therapeutic response to nucleoside analogues. "