Multidrug resistance protein 4 (MRP4) controls tumor growth in a human acute myeloid leukemia in vivo model.

COPSEL S; BRUZZONE A; GARCÍA C; WARGON V; RUSSEL FG; SHAYO C; DAVIO C

Noordwijk aan zee

Congreso; 19th MDO and 12th European ISSX Meeting; 2012

International Society for the Study of Xenobiotics

Multidrug resistance protein 4 (MRP4) controls tumor growth in a human acute myeloid leukemia in vivo model. Authors: Copsel S, Bruzzone A, Garcia C, Wargon V, Russel F, Shayo C, Davio C. Less than a third of adults with acute myeloid leukemia (AML) are cured by current treatments, emphasizing the need for new approaches to therapy. Resistance to drug therapy can arise from increased drug export from tumor cells and/or alterations in intracellular signal transduction. Both mechanisms can be affected by blast expression of members of the multidrug resistance-associated proteins (MRPs). In particular, MRP4/ABCC4 is implicated in cAMP efflux and also confers resistance to nucleoside analogs, cytostatic drugs used in the treatment of AML (1). In addition, it has been reported that MRP4 is expressed in blast cells of patients with AML (2). 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 tumor growth and proliferation in a human AML in vivo model. To investigate the effects of the regulation of cAMP levels on leukemia proliferation we first established U937 subcutaneous chloromas in nu/nu mice. Mice were treated with probenecid (MRP inhibitor, 50 mg/kg), rolipram (phosphodiesterase 4 inhibitor, 1.5 mg/kg), probenecid+rolipram or with vehicle for 2 weeks. Interestingly, all treatments showed an inhibition on tumor growth compared with vehicle-treated mice (P