Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia

Abstract

// Sabrina Copsel 1,2 , Ariana Bruzzone 1 , Maria May 1 , Julien Beyrath 3 , Victoria Wargon 1 , Jeannette Cany 4 , Frans G.M. Russel 3 , Carina Shayo 1 and Carlos Davio 2 1 Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina 2 Laboratorio de Farmacología de Receptores, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina 3 Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands 4 Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Correspondence: Sabrina Copsel, email: // Keywords : acute myeloid leukemia, MRP4/ABCC4, leukemic stem cells, apoptosis, differentiation. Received : May 28, 2014 Accepted : September 02, 2014 Published : September 02, 2014 Abstract Less than a third of adults patients with acute myeloid leukemia (AML) are cured by current treatments, emphasizing the need for new approaches to therapy. We previously demonstrated that besides playing a role in drug-resistant leukemia cell lines, multidrug resistance protein 4 (MRP4/ABCC4) regulates leukemia cell proliferation and differentiation through the endogenous MRP4/ABCC4 substrate, cAMP. Here, we studied the role of MRP4/ABCC4 in tumor progression in a mouse xenograft model and in leukemic stem cells (LSCs) differentiation. We found a decrease in the mitotic index and an increase in the apoptotic index associated with the inhibition of tumor growth when mice were treated with rolipram (PDE4 inhibitor) and/or probenecid (MRPs inhibitor). Genetic silencing and pharmacologic inhibition of MRP4 reduced tumor growth. Furthermore, MRP4 knockdown induced cell cycle arrest and apoptosis in vivo . Interestingly, when LSC population was isolated, we observed that increased cAMP levels and MRP4/ABCC4 blockade resulted in LSCs differentiation. Taken together, our findings show that MRP4/ABCC4 has a relevant role in tumor growth and apoptosis and in the eradication of LSCs, providing the basis for a novel promising target in AML therapy.