Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for
            <i>FLT3</i>
            <i>-</i>
            ITD acute myeloid leukemia

Lam, Simon S. K.; Ho, Esther Sui Chu; He, Bai-Liang; Wong, Wui-Wing; Cher, Chae-Yin; Ng, Nelson Ka Lam; Man, Cheuk-Him; Gill, Harinder; Cheung, Alice; Ip, Ho‐Wan; So, C.C; Tamburini, Jérôme; So, Chi Wai Eric; Ho, Dona N.; Au, Chun Hang; Chan, TM; Edmond, S. K.; Liang, Raymond; Kwong, Yok–Lam; Leung, Anskar Yu Hung

doi:10.1126/scitranslmed.aaf3735

Cited by 66 publications

(66 citation statements)

References 38 publications

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“…To determine if CB-839 will effectively combine with another drug that induces mitochondrial ROS, we next explored homoharringtonine (HHT). HHT is a protein translation inhibitor indicated for the treatment of tyrosine kinase inhibitor-resistant CML (20), which was recently found to effectively combine with FLT3 inhibitors for the treatment of AML (21). We have previously shown that drugs that combine well with FLT3 inhibitors are frequently potent inducers of mitoROS (10).…”

Section: Resultsmentioning

confidence: 99%

Targeting Glutamine Metabolism and Redox State for Leukemia Therapy

Gregory

Nemkov

Park

et al. 2019

Clinical Cancer Research

132

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Purpose: Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically.Experimental Design: AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized.Results: We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) signifi-cantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples, and in vivo using mouse models of AML. In addition, these redoxtargeted combination therapies are effective in eradicating ALL cells in vitro and in vivo.Conclusions: Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.

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Section: Resultsmentioning

confidence: 99%

Targeting Glutamine Metabolism and Redox State for Leukemia Therapy

Gregory

Nemkov

Park

et al. 2019

Clinical Cancer Research

132

View full text Add to dashboard Cite

show abstract

“…To determine if CB-839 will effectively combine with another drug that induces mitochondrial ROS, we next explored homoharringtonine (HHT). HHT is a protein translation inhibitor indicated for the treatment of tyrosine kinase inhibitor-resistant CML 23 that was recently found to effectively combine with FLT3 inhibitors for the treatment of AML 24 . We have previously shown that drugs that combine well with FLT3 inhibitors are frequently potent inducers of mitoROS 14 .…”

Section: Resultsmentioning

confidence: 99%

Targeting glutamine metabolism and redox state for leukemia therapy

Gregory

Nemkov

Zaberezhnyy

et al. 2018

Preprint

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Acute myeloid leukemia (AML) is a hematological malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional genotoxic chemotherapy and a diagnosis of AML is usually fatal.More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. Here, we show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples and in vivo using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating acute lymphoblastic leukemia cells in vitro and in vivo. Thus, targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia. Key Points• Glutaminase inhibition commonly impairs glutathione metabolism and induces mitochondrial oxidative stress in acute myeloid leukemia cells • A glutaminase inhibitor synergizes with pro-oxidant drugs in inducing apoptosis and eliminating leukemia cells in vitro and in vivo Homoharringtonine (HHT; omacetaxine mepesuccinate), arsenic trioxide (ATO), cell-permeable glutathione reduced ethyl ester (GSH-MEE) and dimethyl 2oxoglutarate (α-ketoglutarate) were purchased from Millipore Sigma. Metabolic tracing experimentsCells were seeded at 3 x 10 5 /ml (replicates of 3) and treated with vehicle (DMSO) or CB-839 at 500 nM for 8 h, followed by incubation in glutamine-free RPMI 1640 supplemented with 13 C 5 , 15 N 2 -labeled L-glutamine (Cambridge Isotope Laboratories) for up to 12 h, in the presence of vehicle or drug. Flash frozen cell pellets (~ 1 x 10 6 cells) or supernatants (50 µl) were extracted and subjected to analysis by ultra-high pressure liquid chromatography and mass spectrometry (UHPLC/MS) as was previously described 20 . Metabolite assignments, isotopologue distributions, and correction for expected natural abundances of 13 C and 15 N isotopes were performed using MAVEN (Princeton University, Princeton, NJ) and manually validated. Cell viability assaysCells were seeded at 0.5-1.0 x10 5 /ml in triplicate wells of 48-well tissue culture plates. Where indicated, the cells were treated with drug for a period of 48-72 h.After treatment, a sample of cells from each well was stained with PI (10 µg/ml) and viable cells (PI -) were counted with a flow cytometer (Millipore Guava

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“…For example, homoharringtonine (also known as omocetaxine, synribo) is an inhibitor of the first round of peptide bond formation by the ribosome that has been approved for treatment of tyrosine kinase inhibitor-resistant CML (163) and is currently in clinical trials for AML (43,164,165). Several eukaryotic-specific inhibitors that bind the ribosomal E-site, e.g.…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

How Ribosomes Translate Cancer

et al. 2017

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A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis – from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on “onco-ribosomes” as an Achilles’ heel of cancer cells and a promising target for further therapeutic intervention.

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Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3 - ITD acute myeloid leukemia

Cited by 66 publications

References 38 publications

Targeting Glutamine Metabolism and Redox State for Leukemia Therapy

Targeting Glutamine Metabolism and Redox State for Leukemia Therapy

Targeting glutamine metabolism and redox state for leukemia therapy

How Ribosomes Translate Cancer

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