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.
Highlights
The outcome of therapy for leukemia has improved over the years, less than a third of adults with acute myeloid leukemia (AML) are cured by current treatment, a fact strengthening the need for new therapeutic approaches [1, 2]
Using the gene expression signature associated with vitamin D3-induced differentiation of AML cells, we have identified Emetine as a potential anti-leukemia agent that differentially reduces cell viability and the clonogenic capacity of AML cells sparing healthy blood cells [8]
In order to study the cytotoxic effect of emetine on AML cells, a panel of 5 AML cell lines was treated for 24 h
Summary
The outcome of therapy for leukemia has improved over the years, less than a third of adults with acute myeloid leukemia (AML) are cured by current treatment, a fact strengthening the need for new therapeutic approaches [1, 2]. The knowledge accumulated over the past decades on the nature of leukemic cells indicates that such cells can be converted into non-dividing, growth arrested cells, with a decreased sensitivity to standard chemotherapy [7]. In this regard, it has been established that differentiation of LSCs leads to an inhibition of self-renewal and, a loss of their leukemia initiation capacity [8, 9]. Differentiation therapy constitutes a promising new approach for AML
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