INVESTIGADORES
BRUZZONE Ariana
congresos y reuniones científicas
Título:
Cyclic AMP efflux mediated by Multidrug Resistance Protein 4(MRP4/ABCC4): a new target for the treatment of acute myeloid leukemia.
Autor/es:
COPSEL S; BRUZZONE A; GARCÍA C; WARGON V; RUSSEL FG; SHAYO C; DAVIO C
Lugar:
Bariloche
Reunión:
Simposio; The Second South American Spring Symposium in Signal Transduction and Molecular Medicine; 2012
Institución organizadora:
SISTAM
Resumen:
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<0.01). A
significant decrease in the mitotic index was observed with all the treatments
(P<0.001). Moreover, rolipram+probenecid treatment was even more effective
in decreasing the mitotic index compared with rolipram or probenecid-treated
mice. To further investigate the role of MRP4 in tumor growth, nude mice were
injected with U937 cells expressing shRNA against MRP4 (U937-shMRP4) or scrambled
(U937-scramble). A third group of mice carrying U937-scramble tumor was treated
with rolipram+probenecid. Remarkably, blockage of MRP4 strongly reduced tumor
growth and tumor size was even smaller than in the rolipram+probenecid-treated
group (P<0.05). In addition, a decrease in the mitotic and apoptotic index
was observed. In conclusion, these results show the importance of MRP4 in tumor
growth in a human AML in vivo model, providing the basis for a novel promising
target for leukemia therapy.