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Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer
Open accessAbstract
Arginine, a semi‐essential amino acid in humans, is critical for the growth of human cancers, particularly those marked by de novo chemoresistance and a poor clinical outcome. In addition to protein synthesis, arginine is involved in diverse aspects of tumour metabolism, including the synthesis of nitric oxide, polyamines, nucleotides, proline and glutamate. Tumoural downregulation of the enzyme argininosuccinate synthetase (ASS1), a recognised rate‐limiting step in arginine synthesis, results in an intrinsic dependence on extracellular arginine due to an inability to synthesise arginine for growth. This dependence on extracellular arginine is known as arginine auxotrophy. Several tumours are arginine auxotrophic, due to variable loss of ASS1, including hepatocellular carcinoma, malignant melanoma, malignant pleural mesothelioma, prostate and renal cancer. Importantly, targeting extracellular arginine for degradation in the absence of ASS1 triggers apoptosis in arginine auxotrophs. Several phase I/II clinical trials of the arginine‐lowering drug, pegylated arginine deiminase, have shown encouraging evidence of clinical benefit and low toxicity in patients with ASS1‐negative tumours. In part, ASS1 loss is due to epigenetic silencing of the ASS1 promoter in various human cancer cell lines and tumours, and it is this silencing that confers arginine auxotrophy. In relapsed ovarian cancer, this is associated with platinum refractoriness. In contrast, several platinum sensitive tumours, including primary ovarian, stomach and colorectal cancer, are characterised by ASS1 overexpression, which is regulated by proinflammatory cytokines. This review examines the prospects for novel approaches in the prevention, diagnosis and treatment of malignant disease based on ASS1 pathophysiology and its rate‐limiting product, arginine.
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“For example, some melanoma, lymphoma, glioma, and prostate cancers reduce or lose the expression of the urea cycle enzyme argininosuccinate synthase 1 (ASS1) (Delage et al., 2010).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Delage et al., 2010
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“Accordingly, the auxotrophy of tumors for arginine is being exploited in the development of anticancer therapies (Delage et al., 2010).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Delage et al., 2010
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“Succination is a hallmark of FH-deficient tumours and an antibody against succinate protein has been proposed as a diagnostic marker for HLRCC89.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [89]
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“Succination is a hallmark of FH-deficient tumours and an antibody against succinate protein has been proposed as a diagnostic marker for HLRCC89.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [89]
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Self-citationEfficacy of arginine depletion by ADI-PEG20 in an intracranial model of GBM
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Self-citation
Metadata
- Authors
- Delage, B., Fennell, D. A., Nicholson, L., McNeish, I., Lemoine, N. R., Crook, T., & Szlosarek, P. W.
- Affiliations
- Queen Mary University of London (GB)
- Queen's University Belfast (GB)
- King's College London (GB)
- St Bartholomew's Hospital (GB)
- Imperial College London (GB)
- Corresponding author
- Szlosarek, Peter W.
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2010-04-09
- Volume
- 126
- Issue
- 12
- Pages
- 2762-2772
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W2027449497
- Cited by
- 441
- References
- 86
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 28 · 2023: 30 · 2022: 32 · 2021: 51 · 2020: 26 · 2019: 35 · 2018: 32 · 2017: 26 · 2016: 25 · 2015: 20 · 2014: 25 · 2013: 17 · 2012: 12
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- Cancer Research UK (C12522/A8632, 12008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Keywords
- arginine deprivation, argininosuccinate synthetase, ASS1, arginine auxotrophy, pegylated arginine deiminase, epigenetic silencing, chemoresistance, platinum resistance, ovarian cancer, tumor microenvironment, inflammatory cytokines, hepatocellular carcinoma, melanoma, malignant pleural mesothelioma, prostate cancer, kidney cancer, cancer therapy
- MeSH terms
- Animals, Arginine, Argininosuccinate Synthase, Humans, Neoplasms, Prognosis
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