bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–05–28
nineteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Therapeutic strategies targeting metabolic characteristics of cancer cells.
  2. Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors.
  3. Anaplerotic nutrient stress drives synergy of angiogenesis inhibitors with therapeutics targeting tumor metabolism.
  4. Electron transport chain inhibition increases cellular dependence on purine transport and salvage.
  5. MicroRNAs as regulators of tumor metabolism.
  6. Targeting Oncometabolites in Peritoneal Cancers: Preclinical Insights and Therapeutic Strategies.
  7. α-Ketoglutarate stimulates cell growth through the improvement of glucose and glutamine metabolism in C2C12 cell culture.
  8. Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia.
  9. miRNA-1 promotes acute myeloid leukemia cell pathogenesis through metabolic regulation.
  10. Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss.
  11. Identification of Some Glutamic Acid Derivatives with Biological Potential by Computational Methods.
  12. Glutamate dehydrogenase 1: A novel metabolic target in inhibiting acute myeloid leukaemia progression.
  13. Combination L-Glutamine with Gemcitabine and Nab-Paclitaxel in Treatment-Naïve Advanced Pancreatic Cancer: The Phase I GlutaPanc Study Protocol.
  14. The impact of RNA binding proteins and the associated long non-coding RNAs in the TCA cycle on cancer pathogenesis.
  15. Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
  16. Glycerol as a precursor for hepatic de novo glutathione synthesis in human liver.
  17. Biomimetic Nanoparticle with Glutathione Depletion and Amplified ROS Generation Capabilities for Synergistic Chemo-Sonodynamic Therapy in Squamous Cell Carcinomas.
  18. The role of autophagy in regulating metabolism in the tumor microenvironment.
  19. How to Increase Cellular Glutathione.
  1. Crit Rev Oncol Hematol. 2023 May 24. pii: S1040-8428(23)00125-7. [Epub ahead of print] 104037
    Therapeutic strategies targeting metabolic characteristics of cancer cells.
    Rilan Bai, Ying Meng, Jiuwei Cui.
      Metabolic reprogramming is one of the important characteristics of cancer and is a key process leading to malignant proliferation, tumor development and treatment resistance. A variety of therapeutic drugs targeting metabolic reaction enzymes, transport receptors, and special metabolic processes have been developed. In this review, we investigate the characteristics of multiple metabolic changes in cancer cells, including glycolytic pathways, lipid metabolism, and glutamine metabolism changes, describe how these changes promote tumor development and tumor resistance, and summarize the progress and challenges of therapeutic strategies targeting various links of tumor metabolism in combination with current study data.
    Keywords:  Cancer; Glycolysis; Metabolism; Oxidative Phosphorylation; Treatment Resistance
    DOI:  https://doi.org/10.1016/j.critrevonc.2023.104037
  2. J Immunother Precis Oncol. 2023 May;6(2): 91-102
    Targeting Cancer Metabolism to Improve Outcomes with Immune Checkpoint Inhibitors.
    Zainab Fatima, Abdulrahman Abonofal, Bettzy Stephen.
      Immune checkpoint inhibitors have revolutionized the treatment paradigm of several cancers. However, not all patients respond to treatment. Tumor cells reprogram metabolic pathways to facilitate growth and proliferation. This shift in metabolic pathways creates fierce competition with immune cells for nutrients in the tumor microenvironment and generates by-products harmful for immune cell differentiation and growth. In this review, we discuss these metabolic alterations and the current therapeutic strategies to mitigate these alterations to metabolic pathways that can be used in combination with checkpoint blockade to offer a new path forward in cancer management.
    Keywords:  adenosine pathway; amino acid metabolism; glucose metabolism; immune checkpoint inhibitors; lipid metabolism
    DOI:  https://doi.org/10.36401/JIPO-22-27
  3. bioRxiv. 2023 May 09. pii: 2023.05.07.539744. [Epub ahead of print]
    Anaplerotic nutrient stress drives synergy of angiogenesis inhibitors with therapeutics targeting tumor metabolism.
    Sunada Khadka, Yu-Hsi Lin, Jeffrey Ackroyd, Yi-An Chen, Yanghui Sheng, Wubin Qian, Sheng Guo, Yining Chen, Eliot Behr, Yasaman Barekatain, Md Nasir Uddin, Kenisha Arthur, Victoria Yan, Wen-Hao Hsu, Edward Chang, Anton Poral, Theresa Tran, Surendra Chaurasia, Dimitra K Georgiou, John M Asara, Floris P Barthel, Steve W Millward, Ronald A DePinho, Florian L Muller.
      Tumor angiogenesis is a cancer hallmark, and its therapeutic inhibition has provided meaningful, albeit limited, clinical benefit. While anti-angiogenesis inhibitors deprive the tumor of oxygen and essential nutrients, cancer cells activate metabolic adaptations to diminish therapeutic response. Despite these adaptations, angiogenesis inhibition incurs extensive metabolic stress, prompting us to consider such metabolic stress as an induced vulnerability to therapies targeting cancer metabolism. Metabolomic profiling of angiogenesis-inhibited intracranial xenografts showed universal decrease in tricarboxylic acid cycle intermediates, corroborating a state of anaplerotic nutrient deficit or stress. Accordingly, we show strong synergy between angiogenesis inhibitors (Avastin, Tivozanib) and inhibitors of glycolysis or oxidative phosphorylation through exacerbation of anaplerotic nutrient stress in intracranial orthotopic xenografted gliomas. Our findings were recapitulated in GBM xenografts that do not have genetically predisposed metabolic vulnerabilities at baseline. Thus, our findings cement the central importance of the tricarboxylic acid cycle as the nexus of metabolic vulnerabilities and suggest clinical path hypothesis combining angiogenesis inhibitors with pharmacological cancer interventions targeting tumor metabolism for GBM tumors.
    DOI:  https://doi.org/10.1101/2023.05.07.539744
  4. bioRxiv. 2023 May 11. pii: 2023.05.11.540429. [Epub ahead of print]
    Electron transport chain inhibition increases cellular dependence on purine transport and salvage.
    Zheng Wu, Divya Bezwada, Robert C Harris, Chunxiao Pan, Phong T Nguyen, Brandon Faubert, Ling Cai, Feng Cai, Hieu S Vu, Hongli Chen, Misty Martin- Sandoval, Duyen Do, Wen Gu, Yuannyu Zhang, Bookyung Ko, Bailey Brooks, Sherwin Kelekar, Yuanyuan Zhang, Lauren G Zacharias, K Celeste Oaxaca, Thomas P Mathews, Javier Garcia-Bermudez, Min Ni, Ralph J DeBerardinis.
      Cancer cells reprogram their metabolism to support cell growth and proliferation in harsh environments. While many studies have documented the importance of mitochondrial oxidative phosphorylation (OXPHOS) in tumor growth, some cancer cells experience conditions of reduced OXPHOS in vivo and induce alternative metabolic pathways to compensate. To assess how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts and plasma from patients with inborn errors of mitochondrial metabolism, and in cancer cells subjected to inhibition of the electron transport chain (ETC). All these analyses revealed extensive perturbations in purine-related metabolites; in non-small cell lung cancer (NSCLC) cells, ETC blockade led to purine metabolite accumulation arising from a reduced cytosolic NAD + /NADH ratio (NADH reductive stress). Stable isotope tracing demonstrated that ETC deficiency suppressed de novo purine nucleotide synthesis while enhancing purine salvage. Analysis of NSCLC patients infused with [U- 13 C]glucose revealed that tumors with markers of low oxidative mitochondrial metabolism exhibited high expression of the purine salvage enzyme HPRT1 and abundant levels of the HPRT1 product inosine monophosphate (IMP). ETC blockade also induced production of ribose-5' phosphate (R5P) by the pentose phosphate pathway (PPP) and import of purine nucleobases. Blocking either HPRT1 or nucleoside transporters sensitized cancer cells to ETC inhibition, and overexpressing nucleoside transporters was sufficient to drive growth of NSCLC xenografts. Collectively, this study mechanistically delineates how cells compensate for suppressed purine metabolism in response to ETC blockade, and uncovers a new metabolic vulnerability in tumors experiencing NADH excess.
    DOI:  https://doi.org/10.1101/2023.05.11.540429
  5. Endocr Relat Cancer. 2023 May 01. pii: ERC-22-0267. [Epub ahead of print]
    MicroRNAs as regulators of tumor metabolism.
    Francesca Ruggieri, Katharina Jonas, Manuela Ferracin, Michael Dengler, Vanessa Jager, Martin Pichler.
      Cancer cells reprogram their metabolism to support their growth. Since the discovery of the Warburg effect, several other metabolic alterations and metabolites have been described in cancer cells, including lactate, glutamine and lipid metabolism reprogramming. Together these alterations provide rapidly dividing tumor cells with metabolic intermediates needed for nucleotide, protein and fatty acid biosynthesis. MicroRNAs are a class of small non-coding RNAs involved in the regulation of virtually all biological pathways. Altered microRNA expression patterns are associated with the onset and development of several diseases, including cancer. Tumor suppressor microRNAs targeting molecules involved in tumor metabolism are frequently downregulated in cancers. Therefore, microRNAs can serve as potential tumor biomarkers and also represent interesting therapeutic targets. This review summarizes recent findings about microRNAs involved in the regulation of tumor metabolism.
    DOI:  https://doi.org/10.1530/ERC-22-0267
  6. Metabolites. 2023 Apr 30. pii: 618. [Epub ahead of print]13(5):
    Targeting Oncometabolites in Peritoneal Cancers: Preclinical Insights and Therapeutic Strategies.
    Revathy Nadhan, Srishti Kashyap, Ji Hee Ha, Muralidharan Jayaraman, Yong Sang Song, Ciro Isidoro, Danny N Dhanasekaran.
      Peritoneal cancers present significant clinical challenges with poor prognosis. Understanding the role of cancer cell metabolism and cancer-promoting metabolites in peritoneal cancers can provide new insights into the mechanisms that drive tumor progression and can identify novel therapeutic targets and biomarkers for early detection, prognosis, and treatment response. Cancer cells dynamically reprogram their metabolism to facilitate tumor growth and overcome metabolic stress, with cancer-promoting metabolites such as kynurenines, lactate, and sphingosine-1-phosphate promoting cell proliferation, angiogenesis, and immune evasion. Targeting cancer-promoting metabolites could also lead to the development of effective combinatorial and adjuvant therapies involving metabolic inhibitors for the treatment of peritoneal cancers. With the observed metabolomic heterogeneity in cancer patients, defining peritoneal cancer metabolome and cancer-promoting metabolites holds great promise for improving outcomes for patients with peritoneal tumors and advancing the field of precision cancer medicine. This review provides an overview of the metabolic signatures of peritoneal cancer cells, explores the role of cancer-promoting metabolites as potential therapeutic targets, and discusses the implications for advancing precision cancer medicine in peritoneal cancers.
    Keywords:  aerobic glycolysis; cancer metabolism; metabolite; metabolome; metabolomics; oncometabolite; peritoneal cancers; tumor microenvironment
    DOI:  https://doi.org/10.3390/metabo13050618
  7. Front Nutr. 2023 ;10 1145236
    α-Ketoglutarate stimulates cell growth through the improvement of glucose and glutamine metabolism in C2C12 cell culture.
    Bingquan Yang, Yuefei Liu, Jürgen Michael Steinacker.
       Introduction: Cellular adaptation to physical training and energy metabolism play an important role during physical exercise. This study sought to investigate the effects of α-KG on cell growth and energy metabolism in C2C12 cell culture.
    Methods: C2C12 cells were cultured in media pretreated without (control) or with α-KG at different concentrations, and cells and media were harvested every 24 h for 8 days. From cell counts, specific cell growth rate (SGR) and doubling time were calculated. The content of glucose, glutamine, lactate, and ammonia in media was determined, and the specific consumption rate (SCR) or production rate (SPR) was calculated. Additionally, cell colony-forming efficiency (CFE) was determined.
    Results: The control cells showed a CFE at 50%, a typical cell growth curve in the first 5 days with a mean SGR at 0.86/day, and a mean cell count doubling time at 19.4 h. In the group with α-KG at 100 mM, the cells underwent rapid cell death, and thus no further analysis was made. The treatment with α-KG at lower concentrations (0.1 mM and 1.0 mM) led to a higher CFE at 68 and 55%, respectively, whereas those in groups with higher α-KG concentration decreased (10 and 6% for 20 mM and 30 mM α-KG, respectively). The mean SGR was 0.95/day, 0.94/day, 0.77/day, 0.71/day, and 0.65/day for groups treated with α-KG at 0.1, 1.0, 10.0, 20.0, and 30.0 mM, respectively, and the corresponding cell count doubling time was 17.6, 17.8, 20.9, 24.6, and 24.7 h, respectively. In comparison with that of the control group, the mean glucose SCR decreased in all the groups treated with α-KG, while the mean glutamine SCR remained unchanged; the mean lactate SPR increased in the groups treated with α-KG ≥ 20.0 mM. Finally, the mean SPR of ammonia was lower in all α-KG groups than that in the control.
    Discussion and conclusion: The treatment with α-KG at lower concentrations increased cell growth whereas at higher concentrations decreased cell growth, and α-KG reduced glucose consumption and ammonia production. Therefore, α-KG stimulates cell growth in a dose-dependent manner, which is likely through the improvement of glucose and glutamine metabolism in a C2C12 culture setting.
    Keywords:  C2C12; a-ketoglutarate; ammonia; cell growth; energy metabolism; glucose; glutamin; lactate
    DOI:  https://doi.org/10.3389/fnut.2023.1145236
  8. Front Oncol. 2023 ;13 1161254
    Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia.
    Natalia Timofeeva, Mary L Ayres, Natalia Baran, Janice M Santiago-O'Farrill, Gamze Bildik, Zhen Lu, Marina Konopleva, Varsha Gandhi.
       Introduction: Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species.
    Methods: To investigate the in vitro effects of CB-839 on CLL cells, we tested CB-839 alone and in combination with ibrutinib, venetoclax, or AZD-5991 on the HG-3 and MEC-1 CLL cell lines and on primary CLL lymphocytes.
    Results: We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in the oxygen consumption rate and depletion of the adenosine triphosphate pool and led to the inhibition of cell proliferation. In the cell lines, CB-839 combined with venetoclax or AZD-5991, but not with ibrutinib, demonstrated synergism with an increased apoptosis rate and cell proliferation inhibition. In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed.
    Discussion: Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.
    Keywords:  BTK - Bruton’s tyrosine kinase; Bcl-2 inhibitor; CLL - chronic lymphoblastic leukemia; Mcl-1 inhibitor; glutamine (Gln) metabolism; ibrutinib; venetoclax
    DOI:  https://doi.org/10.3389/fonc.2023.1161254
  9. Front Genet. 2023 ;14 1192799
    miRNA-1 promotes acute myeloid leukemia cell pathogenesis through metabolic regulation.
    Arevik Ghazaryan, Jared A Wallace, William W Tang, Cindy Barba, Soh-Hyun Lee, Kaylyn M Bauer, Morgan C Nelson, Carissa N Kim, Chris Stubben, Warren P Voth, Dinesh S Rao, Ryan M O'Connell.
      Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are both characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). This metabolic shift also led to increased expression of miR-1 in the human AML cell lines tested. AML patient sample datasets showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 promotes OXPHOS through glutaminolysis. Finally, overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Together, our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Further, our work points to miR-1 as a potential new therapeutic target that may be used to disrupt AML cell metabolism and thus pathogenesis in the clinic.
    Keywords:  OxPhos; acute myeloid leukemia; hematological malignancies; microRNA-1; prognostic biomarker
    DOI:  https://doi.org/10.3389/fgene.2023.1192799
  10. Nat Commun. 2023 May 20. 14(1): 2894
    Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss.
    Xianbing Zhu, Zheng Fu, Shary Y Chen, Dionzie Ong, Giulio Aceto, Rebecca Ho, Jutta Steinberger, Anie Monast, Virginie Pilon, Eunice Li, Monica Ta, Kyle Ching, Bianca N Adams, Gian L Negri, Luc Choiniere, Lili Fu, Kitty Pavlakis, Patrick Pirrotte, Daina Z Avizonis, Jeffrey Trent, Bernard E Weissman, Ramon I Klein Geltink, Gregg B Morin, Morag Park, David G Huntsman, William D Foulkes, Yemin Wang, Sidong Huang.
      SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers.
    DOI:  https://doi.org/10.1038/s41467-023-38594-3
  11. Molecules. 2023 May 16. pii: 4123. [Epub ahead of print]28(10):
    Identification of Some Glutamic Acid Derivatives with Biological Potential by Computational Methods.
    Octavia-Laura Moldovan, Alexandra Sandulea, Ioana-Andreea Lungu, Șerban Andrei Gâz, Aura Rusu.
      Glutamic acid is a non-essential amino acid involved in multiple metabolic pathways. Of high importance is its relationship with glutamine, an essential fuel for cancer cell development. Compounds that can modify glutamine or glutamic acid behaviour in cancer cells have resulted in attractive anticancer therapeutic alternatives. Based on this idea, we theoretically formulated 123 glutamic acid derivatives using Biovia Draw. Suitable candidates for our research were selected among them. For this, online platforms and programs were used to describe specific properties and their behaviour in the human organism. Nine compounds proved to have suitable or easy to optimise properties. The selected compounds showed cytotoxicity against breast adenocarcinoma, lung cancer cell lines, colon carcinoma, and T cells from acute leukaemia. Compound 2Ba5 exhibited the lowest toxicity, and derivative 4Db6 exhibited the most intense bioactivity. Molecular docking studies were also performed. The binding site of the 4Db6 compound in the glutamine synthetase structure was determined, with the D subunit and cluster 1 being the most promising. In conclusion, glutamic acid is an amino acid that can be manipulated very easily. Therefore, molecules derived from its structure have great potential to become innovative drugs, and further research on these will be conducted.
    Keywords:  anti-cancer effect; anti-tumour potential; computational methods; glutamic acid; glutamine; molecular docking
    DOI:  https://doi.org/10.3390/molecules28104123
  12. Br J Haematol. 2023 May 25.
    Glutamate dehydrogenase 1: A novel metabolic target in inhibiting acute myeloid leukaemia progression.
    Zhixin Ma, Wenle Ye, Jinghan Wang, Xin Huang, Jiansong Huang, Xia Li, Chao Hu, Chenying Li, Yile Zhou, Xiangjie Lin, Wenwen Wei, Yu Qian, Yutong Zhou, Shihui Mao, Xiufeng Yin, Bo Zhu, Jie Jin.
      Glutamine metabolic reprogramming in acute myeloid leukaemia (AML) cells contributes to the decreased sensitivity to antileukemic drugs. Leukaemic cells, but not their myeloid counterparts, largely depend on glutamine. Glutamate dehydrogenase 1 (GDH1) is a regulation enzyme in glutaminolysis. However, its role in AML remains unknown. Here, we reported that GDH1 was highly expressed in AML: high GDH1 was one of the independent negative prognostic factors in AML cohort. The dependence of leukaemic cells on GDH1 was proved both in vitro and in vivo. High GDH1 promoted cell proliferation and reduced survival time of leukaemic mice. Targeting GDH1 eliminated the blast cells and delayed AML progression. Mechanistically, GDH1 knockdown inhibited glutamine uptake by downregulating SLC1A5. Moreover, GDH1 invalidation also inhibited SLC3A2 and abrogated the cystine-glutamate antiporter system Xc- . The reduced cystine and glutamine disrupted the synthesis of glutathione (GSH) and led to the dysfunction of glutathione peroxidase-4 (GPX4), which maintains the lipid peroxidation homeostasis by using GSH as a co-factor. Collectively, triggering ferroptosis in AML cells in a GSH depletion manner, GDH1 inhibition was synthetically lethal with the chemotherapy drug cytarabine. Ferroptosis induced by inhibiting GDH1 provides an actionable therapeutic opportunity and a unique target for synthetic lethality to facilitate the elimination of malignant AML cells.
    Keywords:  acute myeloid leukaemia; ferroptosis; glutamate dehydrogenase 1; glutathione
    DOI:  https://doi.org/10.1111/bjh.18884
  13. Biomedicines. 2023 May 08. pii: 1392. [Epub ahead of print]11(5):
    Combination L-Glutamine with Gemcitabine and Nab-Paclitaxel in Treatment-Naïve Advanced Pancreatic Cancer: The Phase I GlutaPanc Study Protocol.
    Jun Gong, Arsen Osipov, Jeremy Lorber, Mourad Tighiouart, Albert K Kwan, Hayato Muranaka, Rasaq Akinsola, Sandrine Billet, Abrahm Levi, Anser Abbas, John Davelaar, Neil Bhowmick, Andrew E Hendifar.
      Advanced pancreatic cancer is underscored by progressive therapeutic resistance and a dismal 5-year survival rate of 3%. Preclinical data demonstrated glutamine supplementation, not deprivation, elicited antitumor effects against pancreatic ductal adenocarcinoma (PDAC) alone and in combination with gemcitabine in a dose-dependent manner. The GlutaPanc phase I trial is a single-arm, open-label clinical trial investigating the safety of combination L-glutamine, gemcitabine, and nab-paclitaxel in subjects (n = 16) with untreated, locally advanced unresectable or metastatic pancreatic cancer. Following a 7-day lead-in phase with L-glutamine, the dose-finding phase via Bayesian design begins with treatment cycles lasting 28 days until disease progression, intolerance, or withdrawal. The primary objective is to establish the recommended phase II dose (RP2D) of combination L-glutamine, gemcitabine, and nab-paclitaxel. Secondary objectives include safety of the combination across all dose levels and preliminary evidence of antitumor activity. Exploratory objectives include evaluating changes in plasma metabolites across multiple time points and changes in the stool microbiome pre and post L-glutamine supplementation. If this phase I clinical trial demonstrates the feasibility of L-glutamine in combination with nab-paclitaxel and gemcitabine, we would advance the development of this combination as a first-line systemic option in subjects with metastatic pancreatic cancer, a high-risk subgroup desperately in need of additional therapies.
    Keywords:  L-glutamine; chemotherapy; clinical trial; gemcitabine; metastatic; nab-paclitaxel; pancreatic cancer
    DOI:  https://doi.org/10.3390/biomedicines11051392
  14. RNA Biol. 2023 Jan;20(1): 223-234
    The impact of RNA binding proteins and the associated long non-coding RNAs in the TCA cycle on cancer pathogenesis.
    Tao Shen, Haiyang Wang, Bin Tang, Guoping Zhu, Xiangting Wang.
      The tricarboxylic acid (TCA) cycle is a central route for generating cellular energy and precursors for biosynthetic pathways. Emerging evidences have shown that the aberrations of metabolic enzymes which affect the integrity of TCA cycle are implicated in various tumour pathological processes. Interestingly, several TCA enzymes exhibit the characteristics of RNA binding properties, and their long non-coding RNA (lncRNA) partners play critical regulatory roles in regulating the function of TCA cycle and tumour progression. In this review, we will discuss the functional roles of RNA binding proteins and their lncRNA partners in TCA cycle, with emphasis placed on the cancer progression. A further understanding of RNA binding proteins and their lncRNA partners in TCA cycle, as well as their molecular mechanisms in oncogenesis, will aid in developing novel layers of metabolic targets for cancer therapy in the near future.Abbreviations: CS: citrate synthase. AH: aconitase, including ACO1, and ACO2. IDH: isocitrate dehydrogenase, including IDH1, IDH2, and IDH3. KGDHC: α-ketoglutarate dehydrogenase complex, including OGDH, DLD, and DLST. SCS: succinyl-CoA synthase, including SUCLG1, SUCLG2, and SUCLA2. SDH: succinate dehydrogenase, including SDHA, SDHB, SDHC, and SDHD. FH: fumarate hydratase. MDH: malate dehydrogenase, including MDH1 and MDH2. PC: pyruvate carboxylase. ACLY: ATP Citrate Lyase. NIT: nitrilase. GAD: glutamate decarboxylase. ABAT: 4-aminobutyrate aminotransferase. ALDH5A1: aldehyde dehydrogenase 5 family member A1. ASS: argininosuccinate synthase. ASL: adenylosuccinate synthase. DDO: D-aspartate oxidase. GOT: glutamic-oxaloacetic transaminase. GLUD: glutamate dehydrogenase. HK: hexokinase. PK: pyruvate kinase. LDH: lactate dehydrogenase. PDK: pyruvate dehydrogenase kinase. PDH: pyruvate dehydrogenase complex. PHD: prolyl hydroxylase domain protein.
    Keywords:  RNA binding protein; TCA cycle; TCA cycle enzymes; long non-coding RNA; tumour progression
    DOI:  https://doi.org/10.1080/15476286.2023.2216562
  15. bioRxiv. 2023 May 09. pii: 2023.05.08.539908. [Epub ahead of print]
    Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
    Lara Ibrahim, Caroline Stanton, Kayla Nutsch, Thu Nguyen, Chloris Li-Ma, Yeonjin Ko, Gabriel C Lander, R Luke Wiseman, Michael J Bollong.
      Crosstalk between metabolism and stress-responsive signaling is essential to maintaining cellular homeostasis. One way this crosstalk is achieved is through the covalent modification of proteins by endogenous, reactive metabolites that regulate the activity of key stress-responsive transcription factors such as NRF2. Several metabolites including methylglyoxal, glyceraldehyde 3-phosphate, fumarate, and itaconate covalently modify sensor cysteines of the NRF2 regulatory protein KEAP1, resulting in stabilization of NRF2 and activation of its cytoprotective transcriptional program. Here, we employed a shRNA-based screen targeting the enzymes of central carbon metabolism to identify additional regulatory nodes bridging metabolic pathways to NRF2 activation. We found that succinic anhydride, increased by genetic depletion of the TCA cycle enzyme succinyl-CoA synthetase or by direct administration, results in N-succinylation of lysine 131 of KEAP1 to activate NRF2 transcriptional signaling. This study identifies KEAP1 as capable of sensing reactive metabolites not only by several cysteine residues but also by a conserved lysine residue, indicating its potential to sense an expanded repertoire of reactive metabolic messengers.
    DOI:  https://doi.org/10.1101/2023.05.08.539908
  16. Redox Biol. 2023 May 16. pii: S2213-2317(23)00150-7. [Epub ahead of print]63 102749
    Glycerol as a precursor for hepatic de novo glutathione synthesis in human liver.
    Eunsook S Jin, Craig R Malloy, Gaurav Sharma, Erin Finn, Kelly N Z Fuller, Yesenia Garcia Reyes, Mark A Lovell, Sarkis C Derderian, Jonathan A Schoen, Thomas H Inge, Melanie G Cree.
       BACKGROUND: Glycerol is a substrate for gluconeogenesis and fatty acid esterification in the liver, processes which are upregulated in obesity and may contribute to excess fat accumulation. Glycine and glutamate, in addition to cysteine, are components of glutathione, the major antioxidant in the liver. In principle, glycerol could be incorporated into glutathione via the TCA cycle or 3-phosphoglycerate, but it is unknown whether glycerol contributes to hepatic de novo glutathione biosynthesis.
    METHODS: Glycerol metabolism to hepatic metabolic products including glutathione was examined in the liver from adolescents undergoing bariatric surgery. Participants received oral [U-13C3]glycerol (50 mg/kg) prior to surgery and liver tissue (0.2-0.7g) was obtained during surgery. Glutathione, amino acids, and other water-soluble metabolites were extracted from the liver tissue and isotopomers were quantified with nuclear magnetic resonance spectroscopy.
    RESULTS: Data were collected from 8 participants (2 male, 6 female; age 17.1 years [range 14-19]; BMI 47.4 kg/m2 [range 41.3-63.3]). The concentrations of free glutamate, cysteine, and glycine were similar among participants, and so were the fractions of 13C-labeled glutamate and glycine derived from [U-13C3]glycerol. The signals from all component amino acids of glutathione - glutamate, cysteine and glycine - were strong and analyzed to obtain the relative concentrations of the antioxidant in the liver. The signals from glutathione containing [13C2]glycine or [13C2]glutamate derived from the [U-13C3]glycerol drink were readily detected, and 13C-labelling patterns in the moieties were consistent with the patterns in corresponding free amino acids from the de novo glutathione synthesis pathway. The newly synthesized glutathione with [U-13C3]glycerol trended to be lower in obese adolescents with liver pathology.
    CONCLUSIONS: This is the first report of glycerol incorporation into glutathione through glycine or glutamate metabolism in human liver. This could represent a compensatory mechanism to increase glutathione in the setting of excess glycerol delivery to the liver.
    Keywords:  Cysteine; Glutamate; Glutathione; Glycerol; Glycine; Liver; NMR; Stable isotope
    DOI:  https://doi.org/10.1016/j.redox.2023.102749
  17. ACS Appl Mater Interfaces. 2023 May 23.
    Biomimetic Nanoparticle with Glutathione Depletion and Amplified ROS Generation Capabilities for Synergistic Chemo-Sonodynamic Therapy in Squamous Cell Carcinomas.
    Yunyun Fan, Pengfei Xu, Qi Fang, Yueqiang Zhu, Fei Cao, Zheng Zhao, Di Wu, Xianzhu Yang, Dongdong Li, Xuekui Liu.
      Nanomedicines for combining chemotherapy and sonodynamic therapy (SDT) have enormous potential in squamous cell carcinoma treatment. However, the therapeutic efficacy of noninvasive SDT is severely limited because the generation of reactive oxygen species (ROS) by sonosensitizers is highly dependent on the levels of intracellular excess glutathione (GSH) in the tumor cells. To overcome this barrier, a red blood cell (RBC) membrane-camouflaged nanomedicine consisting of GSH-sensitive polyphosphoester (SS-PPE) and ROS-sensitive polyphosphoester (S-PPE) was designed for the simultaneous delivery of the sonosensitizer hematoporphyrin (HMME) and chemotherapeutic agent docetaxel (DTXL) for effectively enhanced antitumor efficacy. In vitro and in vivo studies demonstrated that HMME-driven ROS generation under ultrasound (US) inhibited SCC7 cell proliferation and accelerated DTXL release to further kill tumor cells via the hydrophobic-hydrophilic transition of the nanoparticle core. Meanwhile, the disulfide bond of SS-PPE effectively consumes GSH to prevent ROS consumption. This biomimetic nanomedicine provides GSH depletion and amplified ROS generation capabilities to achieve a novel synergistic chemo-SDT strategy for squamous cell carcinomas.
    Keywords:  chemo-sonodynamic therapy; glutathione depletion; head and neck cancer; oxidative stress; red blood cell membrane
    DOI:  https://doi.org/10.1021/acsami.3c03792
  18. Genes Dis. 2023 Mar;10(2): 447-456
    The role of autophagy in regulating metabolism in the tumor microenvironment.
    Panpan Zhang, Shanshan Cheng, Xiaonan Sheng, Huijuan Dai, Kang He, Yueyao Du.
      Autophagy, as a special programmed cell death, is a critical degradative process that eliminates intracellular abnormal proteins or damage organelles to balance cell energy and favor cell metabolism with autophagy-related (ATG) proteins. Autophagy activation is being increasingly recognized as an essential hallmark in tumorigenesis through influencing the metabolism of stromal cells in the tumor microenvironment (TME) which comprises of tumor cells, cancer-associated fibroblasts (CAFs), cancer-associated endothelial cells (CAEs), immune cells and adipocytes. Tumor cells can reuse autophagy-involved recycling to maintain mitochondrial function and energy supply to meet the metabolic demand of their growth and proliferation. However, the mechanism through which autophagy can promote a crosstalk between tumor and stroma cells is not clear. Reprogramed metabolism is one of the main characteristics of TME leading to higher adaptability of tumor cells with diverse mechanisms. The activation of autophagy has expanded our understanding on the interaction between tumor metabolism and TME. The aim of this review is to report recent advances on the metabolic cross-talk between stromal cells and solid tumor cells induced by autophagy in TME and revealed potential therapeutic targets.
    Keywords:  Autophagy; Metabolism; Therapeutic targets; Tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.gendis.2021.10.010
  19. Antioxidants (Basel). 2023 May 13. pii: 1094. [Epub ahead of print]12(5):
    How to Increase Cellular Glutathione.
    Daniela Giustarini, Aldo Milzani, Isabella Dalle-Donne, Ranieri Rossi.
      Glutathione (GSH) has special antioxidant properties due to its high intracellular concentration, ubiquity, and high reactivity towards electrophiles of the sulfhydryl group of its cysteine moiety. In most diseases where oxidative stress is thought to play a pathogenic role, GSH concentration is significantly reduced, making cells more susceptible to oxidative damage. Therefore, there is a growing interest in determining the best method(s) to increase cellular glutathione for both disease prevention and treatment. This review summarizes the major strategies for successfully increasing cellular GSH stores. These include GSH itself, its derivatives, NRf-2 activators, cysteine prodrugs, foods, and special diets. The possible mechanisms by which these molecules can act as GSH boosters, their related pharmacokinetic issues, and their advantages and disadvantages are discussed.
    Keywords:  N-acetyl cysteine; Nrf2 activators; cysteine prodrug; glutathione; glutathione boosters; oxidative stress
    DOI:  https://doi.org/10.3390/antiox12051094
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