Multidrug resistance protein 4/ ATP binding cassette transporter 4: a new potential therapeutic target for acute myeloid leukemia
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Sabrina Copsel1,2, Ariana Bruzzone1, Maria May1, Julien Beyrath3, Victoria Wargon1, Jeannette Cany4, Frans G.M. Russel3, Carina Shayo1 and Carlos Davio2
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
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
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.
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