• Biosynthetic enzymes
• Enzyme therapy
• Therapeutic potential
• cancer therapy

• Humans
• Neoplasms/drug therapy
• Enzymes
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Animals

• Humans
• Female
• Carcinoma, Ovarian Epithelial/metabolism
• Carcinoma, Ovarian Epithelial/drug therapy
• Carcinoma, Ovarian Epithelial/pathology
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/pathology
• Tumor Microenvironment/drug effects
• Energy Metabolism/drug effects
• Drug Resistance, Neoplasm
• Immunotherapy
• Animals

• This work was supported by the US National Institutes of Health (R00CA241395 to S.K.), American Cancer Society (DBG-23-1034075-01-DMC to S.K.), and The Kaleidoscope of Hope Ovarian Cancer Foundation (to S.K.).

• Arginine depletion therapy
• Aspartate
• Cancer
• Carbamoyl phosphate
• Urea cycle

• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Urea/metabolism
• Animals
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology

• Aged
• Female
• Humans
• Male
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Arginine/therapeutic use
• Hydrolases
• Lung Neoplasms/drug therapy
• Mesothelioma/drug therapy
• Mesothelioma, Malignant/drug therapy
• Mesothelioma, Malignant/etiology
• Pleural Neoplasms/drug therapy
• Polyethylene Glycols

• P30 CA008748 NCI NIH HHS

• apoptosis
• arginine decarboxylase
• arginine depletion
• argininosuccinate synthetase
• cell-cycle arrest
• colorectal cancer

• Humans
• Animals
• Rats
• Arginase
• Agmatine
• Colonic Neoplasms
• Arginine

• 561709 General Research Fund of RGC
• 1-ZE18 and 1-ZE21 "Project of Strategic Importance" of The Hong Kong Polytechnic University

• ADI-PEG 20
• BCT-100
• arginine auxotrophic cancer
• arginine deprivation cancer therapy
• biomarker
• circulating arginine
• rhArg1-PEG

• CMRPG3M0891 Linkou Chang Gung Memorial Hospital

• Apoptosis
• Arginine depraving factors
• Arginine deprivation
• Autophagy
• Cancer therapy
• Escape mechanisms

• COVID-19
• L-arginine
• autoimmunity
• enzyme-based therapy
• immune response
• immunometabolism
• immunotherapy
• infectious disease
• oncology

• No. 22-24-20013 The research was supported by the grant of the Russian Science Foundation
• No. 45/2022 dated April 14, 2022 Region (grant of St.Peterburg Science Foundation in accordance with the agreement

• 3D culture
• Arginine auxotrophy
• Long-term treatment
• Radiation
• Senescence
• Stemness

• ADI-PEG20
• arginine
• arginine deprivation
• argininosuccinate synthetase 1
• biomarkers
• cancer
• combination therapy
• monotherapy

• Enzymes
• Immunosuppression
• Immunotherapy
• Tumor microenvironment

• Amino acid metabolism
• Arginine
• Asparagine
• Cancer
• Cysteine
• Methionine
• Targeted therapy

• Humans
• Asparagine/metabolism
• Asparagine/therapeutic use
• Cysteine/metabolism
• Neoplasms/metabolism
• Amino Acids/metabolism
• Arginine/metabolism
• Arginine/therapeutic use
• Methionine

• ASS1
• SCLC
• arginine
• arginine deprivation
• argininosuccinate synthase 1
• immunotherapy
• small cell lung cancer
• tumor microenvironment

Background and aims: Vasoactive intestinal polypeptide type-I receptor (VIPR1) overexpression has been reported in numerous types of malignancies and utilized to develop novel target therapeutics and radiolabeled VIP analogue-based tumor imaging technology, but its role in liver carcinogenesis has not been explored. In the current study, we investigated the role of the VIP/VIPR1 signaling in controlling hepatocellular carcinoma (HCC) progression.

Approach and results: By analyzing clinical samples, we found the expression level of VIPR1 was downregulated in human HCC tissues, which was correlated with advanced clinical stages, tumor growth, recurrence, and poor outcomes of HCC clinically. In vitro and in vivo studies revealed that activation of VIPR1 by VIP markedly inhibited HCC growth and metastasis. Intriguingly, transcriptome sequencing analyses revealed that activation of VIPR1 by VIP regulated arginine biosynthesis. Mechanistical studies in cultured HCC cells demonstrated that VIP treatment partially restored the expression of arginine anabolic key enzyme argininosuccinate synthase (ASS1), and to some extent, inhibited de novo pyrimidine synthetic pathway by downregulating the activation of CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). VIP treatment upregulated ASS1 and subsequently suppressed CAD phosphorylation in an mTOR/p70S6K signaling dependent manner. Clinically, we found human HCC samples were associated with downregulation of ASS1 but upregulation of CAD phosphorylation, and that VIPR1 levels positively correlated with ASS1 levels and serum levels of urea, the end product of the urea cycle and arginine metabolism in HCC.

Conclusions: Loss of VIPR1 expression in HCC facilitates CAD phosphorylation and tumor progression, and restoration of VIPR1 and treatment with the VIPR1 agonist may be a promising approach for HCC treatment.

• ASS1
• CAD
• VIPR1
• arginine metabolism
• pyrimidine synthesis

Metabolic reprogramming is an emerging hallmark of tumor cells. In order to survive in the nutrient-deprived environment, tumor cells rewire their metabolic phenotype to provide sufficient energy and build biomass to sustain their transformed state and promote malignant behaviors. Amino acids are the main compositions of protein, which provide key intermediate substrates for the activation of signaling pathways. Considering that cells can synthesize arginine via argininosuccinate synthase 1 (ASS1), arginine is regarded as a non-essential amino acid, making arginine depletion as a promising therapeutic strategy for ASS1-silencing tumors. In this review, we summarize the current knowledge of expression pattern of ASS1 and related signaling pathways in cancer and its potential role as a novel therapeutic target in cancer. Besides, we outline how ASS1 affects metabolic regulation and tumor progression and further discuss the role of ASS1 in arginine deprivation therapy. Finally, we review approaches to target ASS1 for cancer therapies.

• amino acid metabolism
• cancer
• cancer–nerve crosstalk
• lactate
• metabolites
• perineural invasion
• tumor innervation
• vitamins

• Cell Proliferation
• Glucose/metabolism
• Humans
• Lactates
• Neoplasms/metabolism
• Vitamins

• P20 GM139768 NIGMS NIH HHS
• 1P20GM139768-01 sub5741 NIH HHS

Metabolic disorder is a key factor in the occurrence and development of tumors. Metabolomics methods can explore a variety of prognostic markers for tumors.

The 454 patients included in this study comprised 92 cases of gastric cancer, 51 cases of gastric ulcers, 206 cases of gastric polyps, and 105 cases of gastritis. The plasma levels of 23 amino acids in patients before treatment were detected by liquid chromatography-tandem mass spectrometry, and t-test was used to determine the difference of amino acids levels between the gastric cancer group and other groups. Shared different amino acids were selected to analyze their relationship with staging, differentiation and prognosis. The TCGA database was used to explore the changes of genes expression related to the synthesis and degradation of different amino acids, and the relationship between the genes and stage, differentiation and prognosis.

The plasma arginine level in the gastric cancer group was significantly higher than that in the gastric ulcer, gastric polyp, and gastritis groups (P values 0.0065, 0.0306, 0.0004, respectively).The level of plasma arginine in patients with non-metastatic gastric cancer was significantly higher than that in patients with metastatic gastric cancer (P=0.0013). Compared with the normal control, the key metabolic enzyme ASS1 gene was highly expressed in gastric cancer, and the survival time of gastric cancer patients with high expression of ASS1 was longer. Patients with high arginine expression had significantly longer survival (log-rank test P=0.0003).

Increased plasma arginine level in gastric cancer patients was related to overexpression of ASS1 by TCGA database analysis. High expression of ASS1 prolonged the overall survival of gastric cancer patients, and the arginine level before treatment could be used as a prognostic factor.

• Gastric cancer
• arginine
• metabolomics
• prognosis

• Apoptosis
• Autophagy
• BCA-M-PEG20
• Cell cycle arrest Cytostatic

Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.

• GBM-glioblastoma multiforme
• HCC-hepatocellular carcinoma
• PDAC-pancreatic ductal adenocarcinoma
• amino acid
• cancer stem cell (CSC)
• glucose
• therapy

• amino acid depletion
• amino acid metabolism
• cancer
• cancer therapy
• metabolic reprogramming

Background: We previously reported that severe COVID-19 patients had higher chances of survival and a reduced risk of developing respiratory failure when administered with the probiotic formulation SLAB51. This study aimed to investigate further bacteriotherapy mechanisms and how early they are activated. Methods: We performed an analysis on the blood oxygenation parameters collected in sixty-nine severe COVID-19 patients requiring non-invasive oxygen therapy and presenting a CT lung involvement ≥50%. Twenty-nine patients received low-molecular-weight heparin, azithromycin and Remdesivir. In addition, forty subjects received SLAB51. Blood gas analyses were performed before the beginning of treatments and at 24 h. Results: The patients receiving only standard therapy needed significantly increased oxygen amounts during the 24 h observation period. Furthermore, they presented lower blood levels of pO₂, O₂Hb and SaO₂ than the group also supplemented with oral bacteriotherapy. In vitro data suggest that SLAB51 can reduce nitric oxide synthesis in intestinal cells. Conclusions: SARS-CoV-2 infected patients may present lesions in the lungs compromising their gas exchange capability. The functionality of the organs essential for these patients’ survival depends mainly on the levels of pO₂, O₂Hb and SaO₂. SLAB51 contains enzymes that could reduce oxygen consumption in the intestine, making it available for the other organs.

• COVID-19
• SLAB51
• hypoxia
• nitric oxide
• probiotics

• arginine
• fluorouracil, leucovorin, and oxaliplatin (FOLFOX)
• hepatocellular carcinoma
• pegylated arginine deiminase (ADI-PEG 20)
• phase 2

• Arginase
• Arginine decarboxylase
• Arginine deiminase
• Argininosuccinate synthetase
• Auxotrophic cancer
• Deprivation therapy
• Therapeutic enzyme

• Advanced Solid Tumors
• Arginase
• Arginine
• PEG-BCT-100

• ADI-PEG20
• TRAIL
• apoptosis
• arginine deprivation therapy
• autophagy
• melanoma
• rhArg

• Apoptosis/drug effects
• Arginine/deficiency
• Arginine/metabolism
• Autophagy/drug effects
• Cell Line, Tumor
• Drug Resistance, Neoplasm/drug effects
• Humans
• Hydrolases/metabolism
• Hydrolases/pharmacology
• Melanoma/metabolism
• Polyethylene Glycols/metabolism
• Polyethylene Glycols/pharmacology
• Signal Transduction/drug effects
• TNF-Related Apoptosis-Inducing Ligand/genetics
• TNF-Related Apoptosis-Inducing Ligand/metabolism
• TNF-Related Apoptosis-Inducing Ligand/pharmacology

• I01 BX004371 BLRD VA
• I01 BX005051 BLRD VA
• IK2 BX001289 BLRD VA
• 101BX003328-01 U.S. Department of Veterans Affairs

• ADI-PEG 20
• Arginine
• arginine deiminase
• argininosuccinate synthetase-1
• cancer
• cd-3
• citrulline
• pd-l1
• pembrolizumab
• tumor immunity

• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Humans
• Hydrolases
• Neoplasms/drug therapy
• Polyethylene Glycols
• Tumor Microenvironment

• GCN2
• general control non-derepressible 2
• mTORC1
• myeloid leukemias
• non-essential amino acid

• R01 CA216815 NCI NIH HHS

• Snail
• argininosuccinate synthase 1
• epithelial-mesenchymal transition
• metastasis
• ubiquitination

• arginine
• arginine deiminase
• citrulline
• swine
• tracer kinetics

• Animals
• Arginine/blood
• Arginine/pharmacokinetics
• Biological Availability
• Citrulline/blood
• Female
• Hydrolases/pharmacology
• Kinetics
• Male
• Polyethylene Glycols/pharmacology
• Swine
• Tissue Distribution/drug effects

• R01 GM108940 NIGMS NIH HHS

• Arginine deiminase
• Arginine deprivation therapy
• Human arginase
• Protein engineering

Globally, hepatocellular carcinoma (HCC) is a leading cause of cancer and cancer-related deaths. The therapeutic efficacy of locoregional and systemic treatment in patients with advanced HCC remains low, which results in a poor prognosis. The development of sorafenib for the treatment of HCC has resulted in a new era of molecular targeted therapy for this disease. However, the median overall survival was reported to be barely higher in the sorafenib treatment group than in the control group. Hence, in this review we describe the importance of developing more effective targeted therapies for the management of advanced HCC. Recent investigations of molecular signaling pathways in several cancers have provided some insights into developing molecular therapies that target critical members of these signaling pathways. Proteins involved in the Hedgehog and Notch signaling pathways, Polo-like kinase 1, arginine, histone deacetylases and Glypican-3 can be potential targets in the treatment of HCC. Monotherapy has limited therapeutic efficacy due to the development of inhibitory feedback mechanisms and induction of chemoresistance. Thus, emphasis is now on the development of personalized and combination molecular targeted therapies that can serve as ideal therapeutic strategies for improved management of HCC.

• Hepatocellular carcinoma
• Prognosis
• Arginine deprivation
• Cancer stem cells
• Glypican-3
• Hedgehog signaling pathway
• Histone deacetylases
• Personalized medicine
• Molecular targeted therapy
• Notch signaling pathway
• Polo-like kinase 1
• Tumour-associated antigens

For the past 100 years, oncologists have relentlessly pursued the destruction of tumor cells by surgical, chemotherapeutic or radiation oncological means. Consistent with this focus, treatment plans are typically based on key characteristics of the tumor itself such as disease site, histology and staging based on local, regional and systemic dissemination. Precision medicine is similarly built on the premise that detailed knowledge of molecular alterations of tumor cells themselves enables better and more effective tumor cell destruction. Recently, host factors within the tumor microenvironment including the vasculature and immune systems have been recognized as modifiers of disease progression and are being targeted for therapeutic gain. In this review, we argue that—to optimize the impact of old and new treatment options—we need to take account of an epidemic that occurs independently of—but has major impact on—the development and treatment of malignant diseases. This is the rapidly increasing number of patients with excess weight and its’ attendant metabolic consequences, commonly described as metabolic syndrome. It is well established that patients with altered metabolism manifesting as obesity, metabolic syndrome and chronic inflammation have an increased incidence of cancer. Here, we focus on evidence that these patients also respond differently to cancer therapy including radiation and provide a perspective how exercise, diet or pharmacological agents may be harnessed to improve therapeutic responses in this patient population.

• caloric restriction
• cancer therapy
• dietary interventions
• host metabolism
• obesity
• radiation

• ADI-PEG 20
• Argininosuccinate synthetase 1
• Auxotropy
• Biomarker
• SCLC

• T lymphocyte
• T-cell metabolism
• arginase
• arginine
• immunosuppression
• immunotherapy
• tumor immunology

• Animals
• Antineoplastic Agents/therapeutic use
• Arginase/antagonists & inhibitors
• Arginase/immunology
• Arginine/metabolism
• Clinical Trials as Topic
• Humans
• Macrophages/immunology
• Mice
• Myeloid Cells/enzymology
• Myeloid Progenitor Cells/metabolism
• Neoplasms/drug therapy
• Neoplasms/immunology

Arginine deprivation cancer therapy targets certain types of malignancies with positive result in many studies and clinical trials. NEI-01 was designed as a novel arginine-depleting enzyme comprising an albumin binding domain capable of binding to human serum albumin to lengthen its half-life. In the present work, NEI-01 is shown to bind to serum albumin from various species, including mice, rat and human. Single intraperitoneal administration of NEI-01 to mice reduced plasma arginine to undetectable level for at least 9 days. Treatment of NEI-01 specifically inhibited cell viability of MIA PaCa-2 and PANC-1 cancer cell lines, which were ASS1 negative. Using a human pancreatic mouse xenograft model, NEI-01 treatment significantly reduced tumor volume and weight. Our data provides proof of principle for a cancer treatment strategy using NEI-01.

Arginase has therapeutic potential as a cytotoxic agent in some cancers, but this is unclear for precursor B acute lymphoblastic leukaemia (pre-B ALL), the commonest form of childhood leukaemia. We compared arginase cytotoxicity with asparaginase, currently used in pre-B ALL treatment, and characterised the forms of cell death induced in a pre-B ALL cell line 697. Arginase and asparaginase both efficiently killed 697 cells and mature B lymphoma cell line Ramos, but neither enzyme killed normal lymphocytes. Arginase depleted cellular arginine, and arginase-treated media induced cell death, blocked by addition of arginine or arginine-precursor citrulline. Asparaginase depleted both asparagine and glutamine, and asparaginase-treated media induced cell death, blocked by asparagine, but not glutamine. Both enzymes induced caspase cleavage and activation, chromatin condensation and phosphatidylserine exposure, indicating apoptosis. Both arginase- and asparaginase-induced death were blocked by caspase inhibitors, but with different sensitivities. BCL-2 overexpression inhibited arginase- and asparaginase-induced cell death, but did not prevent arginase-induced cytostasis, indicating a different mechanism of growth arrest. An autophagy inhibitor, chloroquine, had no effect on the cell death induced by arginase, but doubled the cell death induced by asparaginase. In conclusion, arginase causes death of lymphoblasts by arginine-depletion induced apoptosis, via mechanism distinct from asparaginase. Therapeutic implications for childhood ALL include: arginase might be used as treatment (but antagonised by dietary arginine and citrulline), chloroquine may enhance efficacy of asparaginase treatment, and partial resistance to arginase and asparaginase may develop by BCL-2 expression. Arginase or asparaginase might potentially be used to treat Burkitt lymphoma.

• Apoptosis
• Arginase
• Asparaginase
• Cell death
• Leukaemia

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Apoptosis/drug effects
• Arginase/pharmacology
• Arginase/physiology
• Arginase/therapeutic use
• Asparaginase/pharmacology
• Asparaginase/physiology
• Asparaginase/therapeutic use
• Cell Death/drug effects
• Cell Line, Tumor
• Child
• Humans
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
• Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
• Precursor Cells, B-Lymphoid/drug effects
• Precursor Cells, B-Lymphoid/physiology

• 10027 Bloodwise

• Arginine
• Cancer
• Deprivation
• Metabolism

• Cancer
• Metabolic waste
• Metabolism
• Metastasization
• Therapy
• Tumour microenvironment

• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Dose-Response Relationship, Drug
• Humans
• Molecular Structure
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Structure-Activity Relationship
• Tumor Microenvironment/drug effects

• Amino acid degrading enzymes
• L-arginine deiminase
• L-asparaginase
• L-lysine α-oxidase
• L-methionine γ-lyase
• cancer therapy
• cancer treatment.

• arginine
• asparagine
• aspartate
• cancer
• cysteine
• glutamate
• glutamine
• glycine
• proline
• serine

• Arginase
• Cytokeratin 19
• Differentiation
• Hepatocellular carcinoma
• Liver
• Recurrence
• Surgery
• Survival