Cyclic AMP efflux mediated by Multidrug Resistance Protein 4(MRP4/ABCC4): a new target for the treatment of acute myeloid leukemia.

COPSEL SABRINA; BRUZZONE ARIANA; GARCIA CORINA; WARGON V; RUSSEL FG; SHAYO CARINA; DAVIO CARLOS

Bariloche.

Simposio; South American spring Symposium in Signal Trasducction and Molecular Medicine. (SISTAM 2012).; 2012

Cyclic AMP efflux mediated by Multidrug Resistance Protein 4(MRP4/ABCC4): a new target for the treatment of acute myeloid leukemia. Copsel S1,2, Bruzzone A2, Garcia C1, Wargon V2, Russel FG3, Shayo C2, Davio C1 1Laboratorio de Farmacología de Receptores, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina. 2Instituto de Biología y Medicina Experimental, IBYME-CONICET, Buenos Aires, Argentina. 3Deptartment of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Less than a third of adults with acute myeloid leukemia (AML) are cured by current treatments, emphasizing the need for new approaches to therapy. We have recently demonstrated in AML cell lines that MRP4 has a relevant role in the regulation of intracellular cAMP levels, leading to the inhibition of cell proliferation and promoting differentiation. Thus, we have postulated that the inhibition of cAMP efflux by blocking MRPs, mainly MRP4, may lead to a decrease in proliferation and tumor growth. To test this, a human AML model was established by subcutaneous injection of U937 cells into nude mice. In order to investigate the effect of the regulation of cAMP levels, mice were treated with probenecid (MRP inhibitor), rolipram (PDE4 inhibitor), probenecid+rolipram or vehicle. Interestingly, all treatments showed an inhibition on tumor growth compared with vehicle-treated mice (P