Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells

Abstract

// Josep Maria Cornet-Masana 1 , Daniel Moreno-Martínez 1 , María Carmen Lara-Castillo 1 , Meritxell Nomdedeu 1,2 , Amaia Etxabe 1 , Niccolò Tesi 1 , Marta Pratcorona 1,2 , Jordi Esteve 1,2 and Ruth M. Risueño 1 1 Josep Carreras Leukaemia Research Institute, Barcelona, Spain 2 Department of Hematology, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Correspondence to: Ruth M. Risueño, email: // Keywords : AML, emetine, anti-leukemia drug Received : February 24, 2016 Accepted : February 28, 2016 Published : March 15, 2016 Abstract Acute myeloid leukemia (AML) is an hematologic neoplasia characterized by the accumulation of transformed immature myeloid cells in bone marrow. Although the response rate to induction therapy is high, survival rate 5-year after diagnosis is still low, highlighting the necessity of new novel agents. To identify agents with the capability to abolish the self-renewal capacity of AML blasts, an in silico screening was performed to search for small molecules that induce terminal differentiation. Emetine, a hit compound, was validated for its anti-leukemic effect in vitro , ex vivo and in vivo . Emetine, a second-line anti-protozoa drug, differentially reduced cell viability and clonogenic capacity of AML primary patient samples, sparing healthy blood cells. Emetine treatment markedly reduced AML burden in bone marrow of xenotransplanted mice and decreased self-renewal capacity of the remaining engrafted AML cells. Emetine also synergized with commonly used chemotherapeutic agents such as ara-C. At a molecular level, emetine treatment was followed by a reduction in HIF-1α protein levels. This study validated the anti-leukemiceffect of emetine in AML cell lines, a group of diverse AML primary samples, and in a human AML-transplanted murine model, sparing healthy blood cells. The selective anti-leukemic effect of emetine together with the safety of the dose range required to exert this effect support the development of this agent in clinical practice.