Metabolic Differences in Glutamine Utilization Lead to Metabolic Vulnerabilities in Prostate Cancer

Zacharias, Nikolaos; McCullough, Christopher; Shanmugavelandy, Sriram S.; Lee, Jae-Hyuk; Lee, Youngbok; Dutta, Prasanta; McHenry, James; Nguyen, Linda; Norton, William; Jones, L. W.; Bhattacharya, Pratip K.

doi:10.1038/s41598-017-16327-z

Cited by 58 publications

(46 citation statements)

References 54 publications

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“…There are other hematologic malignancies, such as multiple myeloma, which have been reported to be highly dependent on glutamine metabolism for survival (36,37). Furthermore, subsets of many solid tumor types, including lung, breast, kidney, and prostate cancer, have been shown to be susceptible to glutaminase inhibition (38)(39)(40)(41)(42)(43). Therefore, the use of a glutaminase inhibitor in combination with a pro-oxidant drug could represent a strategy with broad therapeutic utility in the treatment of various cancers.…”

Section: Discussionmentioning

confidence: 99%

Targeting Glutamine Metabolism and Redox State for Leukemia Therapy

Gregory

Nemkov

Park

et al. 2019

Clinical Cancer Research

115

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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: Discussionmentioning

confidence: 99%

Targeting Glutamine Metabolism and Redox State for Leukemia Therapy

Gregory

Nemkov

Park

et al. 2019

Clinical Cancer Research

115

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“…Other hematological malignancies, such as multiple myeloma, have been reported to be highly dependent on glutamine metabolism 33,34 . Furthermore, subsets of many solid tumor types, including lung, breast, kidney, and prostate cancer, have been shown to be susceptible to glutaminase inhibition [35][36][37][38][39][40] . Therefore, the use of a glutaminase inhibitor in combination with a pro-oxidant drug could represent a strategy with broad therapeutic utility in the treatment of cancer.…”

Section: Discussionmentioning

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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“…Since several oncogenes regulate GLS expression and many studies have shown that cancer cells are GLSdependent 3,9,10 , GLS inhibitors (GLSi) (have been designed and evaluated in preclinical and clinical trials for brain tumors (trial ID: NCI-2018-00876) [11][12][13] . The specific and orally bioavailable small molecule inhibitor CB839 has been shown to effectively reduce viability, chemosensitivity, and induce apoptosis in several tumor entities including breast, ovarian, prostate, and lung cancer [14][15][16][17] . Furthermore, compound 968 (C968), another small molecule GLS inhibitor, has been reported to impair tumor cell clonogenicity, viability, and growth [18][19][20][21][22][23] .…”

Section: Introductionmentioning

confidence: 99%

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

et al. 2020

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Cancer cells upregulate anabolic processes to maintain high rates of cellular turnover. Limiting the supply of macromolecular precursors by targeting enzymes involved in biosynthesis is a promising strategy in cancer therapy. Several tumors excessively metabolize glutamine to generate precursors for nonessential amino acids, nucleotides, and lipids, in a process called glutaminolysis. Here we show that pharmacological inhibition of glutaminase (GLS) eradicates glioblastoma stem-like cells (GSCs), a small cell subpopulation in glioblastoma (GBM) responsible for therapy resistance and tumor recurrence. Treatment with small molecule inhibitors compound 968 and CB839 effectively diminished cell growth and in vitro clonogenicity of GSC neurosphere cultures. However, our pharmaco-metabolic studies revealed that only CB839 inhibited GLS enzymatic activity thereby limiting the influx of glutamine derivates into the TCA cycle. Nevertheless, the effects of both inhibitors were highly GLS specific, since treatment sensitivity markedly correlated with GLS protein expression. Strikingly, we found GLS overexpressed in in vitro GSC models as compared with neural stem cells (NSC). Moreover, our study demonstrates the usefulness of in vitro pharmacometabolomics to score target specificity of compounds thereby refining drug development and risk assessment.

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Metabolic Differences in Glutamine Utilization Lead to Metabolic Vulnerabilities in Prostate Cancer

Cited by 58 publications

References 54 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

A comparative pharmaco-metabolomic study of glutaminase inhibitors in glioma stem-like cells confirms biological effectiveness but reveals differences in target-specificity

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