Emetine induces chemosensitivity and reduces clonogenicity of acute myeloid leukemia cells

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.

Repositioning of bromocriptine for treatment of acute myeloid leukemia

“…Gene signature associated with PMA (phorbol myristate acetate)-induced differentiation in HL60 cells was obtained from GSE982 and analysed as described previously (vehicle-control treated vs. PMA-treated samples) [ 10 , 11 ]. Briefly, raw files (.cel) were normalized using GenePattern software (Broad Institute Cancer Program; http://www.broadinstitute.org/cancer/software/genepattern/ ) and probe set with a differential expression of at least twofold of change and p value below 0.005 were chosen.…”

Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism

“…Since it has been reported that emetine suppresses the expression of HIF-1α, which is a key regulator of glucose metabolism, [ 26 – 29 ] we evaluated HIF-1α expression in the tumor cells using western blotting. [ 30 , 31 ] HIF-1α expression in the tumor cells was suppressed by treatment of the cells with 0.5 μM emetine in the presence of CoCl 2 , which was used to mimic a hypoxia condition and by treatment of cells grown under the condition of 5% O 2 hypoxia for 48 h (Figure 4B and Supplemental Figure S3C ). Taking into account the fact that emetine inhibited the promotion of glycolysis in tumor cells that was mediated by CAF as described above, we considered that emetine might suppress glycolysis in tumor cells, which would result in apoptosis of the tumor cells.…”

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

“…Some of these compounds have shown good chemosensitizing effects. In several preclinical models of solid and hematologic tumors, direct inhibitors of HIF-1α, such as YC-1 [ 103 ] and BAY87-2243 [ 189 ], or indirect down-regulators of HIF-1α signalling, as the anti-androgen dutasteride [ 190 ], the alkaloid emetine [ 191 ], the lncRNA HITT [ 192 ] – one of the multiple ncRNA that regulate HIF-1α [ 193 ] –, have induced chemosensitization, by reducing HIF-1α transcriptional activity. The disadvantage of these inhibitors is their aspecificity.…”