Proteolytic systems and AMP-activated protein kinase are critical targets of acute myeloid leukemia therapeutic approaches

// Ângela Fernandes 1,2,* , Maria M. Azevedo 1,2,* , Olga Pereira 1,2 , Belem Sampaio-Marques 1,2 , Artur Paiva 3 , Margarida Correia-Neves 1,2 , Isabel Castro 1,2 and Paula Ludovico 1,2 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal 2 ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimaraes, Portugal 3 Blood and Transplantation Center of Coimbra, Portuguese Institute of Blood and Transplantation, Coimbra, Portugal * These authors contributed equally to this work Correspondence: Paula Ludovico, email: // Keywords : acute myeloid leukemia (AML), macroautophagy, ubiquitin-proteasome system (UPS), AMPK pathway, chemotherapeutic agents Received : September 30, 2014 Accepted : December 09, 2014 Published : December 10, 2014 Abstract The therapeutic strategies against acute myeloid leukemia (AML) have hardly been modified over four decades. Although resulting in a favorable outcome in young patients, older individuals, the most affected population, do not respond adequately to therapy. Intriguingly, the mechanisms responsible for AML cells chemoresistance/susceptibility are still elusive. Mounting evidence has shed light on the relevance of proteolytic systems (autophagy and ubiquitin-proteasome system, UPS), as well as the AMPK pathway, in AML biology and treatment, but their exact role is still controversial. Herein, two AML cell lines (HL-60 and KG-1) were exposed to conventional chemotherapeutic agents (cytarabine and/or doxorubicin) to assess the relevance of autophagy and UPS on AML cells’ response to antileukemia drugs. Our results clearly showed that the antileukemia agents target both proteolytic systems and the AMPK pathway. Doxorubicin enhanced UPS activity while drugs’ combination blocked autophagy specifically on HL-60 cells. In contrast, KG-1 cells responded in a more subtle manner to the drugs tested consistent with the higher UPS activity of these cells. In addition, the data demonstrates that autophagy may play a protective role depending on AML subtype. Specific modulators of autophagy and UPS are, therefore, promising targets for combining with standard therapeutic interventions in some AML subtypes.