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

COPSEL S; BRUZZONE A; GARCIA C; WARGON V; RUSSEL FGM; SHAYO C; DAVIO C

Barilche

Simposio; The Second South American Spring Symposium in Signal Trasduction and Molecular Medicine; 2012

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. A significant decrease in the mitotic index was observed with all the treatments. 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 reduces tumor growth and tumor size was even smaller than in the rolipram+probenecid-treated group. In addition, a decrease in the mitotic and apoptotic index was observed. In conclusion, these results show for 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