The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase
Open accessAbstract
Eukaryotic cells can synthesize the non-essential amino acid arginine from aspartate and citrulline using the enzyme argininosuccinate synthetase (ASS). It has been observed that ASS is underexpressed in various types of cancers ASS, for which arginine become auxotrophic. Arginine deiminase (ADI) is a prokaryotic enzyme that metabolizes arginine to citrulline and has been found to inhibit melanoma and hepatoma cancer cells deficient of ASS. We tested the hypothesis that pancreatic cancers have low ASS expression and therefore arginine deprivation by ADI will inhibit cell growth. ASS expression was examined in 47 malignant and 20 non-neoplastic pancreatic tissues as well as a panel of human pancreatic cancer cell lines. Arginine deprivation was achieved by treatment with a recombinant form of ADI formulated with polyethylene glycol (PEG-ADI). Effects on caspase activation, cell growth and cell death were examined. Furthermore, the effect of PEG-ADI on the in vivo growth of pancreatic xenografts was examined. Eighty-seven percent of the tumors lacked ASS expression; 5 of 7 cell lines similarly lacked ASS expression. PEG-ADI specifically inhibited growth of those cell lines lacking ASS. PEG-ADI treatment induced caspase activation and induction of apoptosis. PEG-ADI was well tolerated in mice despite complete elimination of plasma arginine; tumor growth was inhibited by approximately 50%. Reduced expression of ASS occurs in pancreatic cancer and predicts sensitivity to arginine deprivation achieved by PEG-ADI treatment. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of pancreatic cancer, a malignancy in which new therapy is desperately needed.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Intriguingly, both ASS1 and ASL enzymes are frequently epigenetically silenced in melanoma, renal cell carcinoma and hepatocellular carcinoma (Bowles et al., 2008; Ensor et al., 2002; Yoon et al., 2007).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Bowles et al., 2008
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Autophagy as a Regulated Pathway of Cellular Degradation
Klionsky, D. J., & Emr, S. D. (2000) · Science · doi:10.1126/science.290.5497.1717 · Cited by 3,630
Autophagy: from phenomenology to molecular understanding in less than a decade
Klionsky, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2245 · Cited by 1,977
Autophagy as a cell death and tumor suppressor mechanism
Gözüaçık, D., & Kimchi, A. (2004) · Oncogene · doi:10.1038/sj.onc.1207521 · Cited by 1,396
Another way to die: autophagic programmed cell death
Tsujimoto, Y., & Shimizu, S. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401777 · Cited by 765
Almost all about citrulline in mammals
Curis, E., Nicolis, I., Moinard, C., Osowska, S., Zerrouk, N., Bénazeth, S., & Cynober, L. (2005) · Amino Acids · doi:10.1007/s00726-005-0235-4 · Cited by 571
Autophagy delays apoptotic death in breast cancer cells following DNA damage
Abedin, M. J., Wang, D.-P., McDonnell, M. A., Lehmann, U., & Kelekar, A. (2006) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402039 · Cited by 532
The Roles of Therapy-Induced Autophagy and Necrosis in Cancer Treatment
Amaravadi, R. K., & Thompson, C. B. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1595 · Cited by 474
Enzymes of Arginine Metabolism
Morris, S. M. (2004) · Journal of Nutrition · doi:10.1093/jn/134.10.2743s · Cited by 361
Argininosuccinate synthetase from the urea cycle to the citrulline–NO cycle
Husson, A., Brasse‐Lagnel, C., Fairand, A., Renouf, S., & Lavoinne, A. (2003) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2003.03559.x · Cited by 335
Ensor, M., Holtsberg, F. W., Bomalaski, J. S., & Clark, M. A. (2002) · PubMed · Cited by 315
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–153 of 153
Yu, K.-M., Pang, T. P. S., Cutler, M. J., Tian, M., Huang, L. Y. L., Lau, J. Y., Chung, S., Lo, T. W.-H., & Leung, T. Y.-C. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118674 · Cited by 14
Kurlishchuk, Y. V., Vynnytska‐Myronovska, B., Grosse‐Gehling, P., Bobak, Y. P., Manig, F., Chen, O., Merker, S. R., Henle, T., Löck, S., Stange, D. E., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.12320 · Cited by 14
Glazer, E. S., Kaluarachchi, W. D., Massey, K. L., Zhu, C., & Curley, S. A. (2010) · Surgery · doi:10.1016/j.surg.2010.03.022 · Cited by 13
A modified arginine-depleting enzyme NEI-01 inhibits growth of pancreatic cancer cells
Chow, J. P. H., Cai, Y., Chow, D. T. L., Chung, S. H. K., Chau, K.-C., Ng, K.-Y., Leung, O. M., Wong, R. M. H., Law, A. W. L., Leung, Y.-O., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0231633 · Cited by 12
Wu, C., You, M., Nguyen, D. M., Wangpaichitr, M., Li, Y., Feun, L. G., Kuo, M. T., & Savaraj, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147628 · Cited by 12
Arginine enzymatic deprivation and diet restriction for cancer treatment
Zam, W. (2017) · Brazilian Journal of Pharmaceutical Sciences · doi:10.1590/s2175-97902017000300200 · Cited by 12
Yuan, Y., Mohammad, M. A., Betancourt, A., Didelija, I. C., Yallampalli, C., & Marini, J. C. (2018) · Journal of Nutrition · doi:10.1093/jn/nxy065 · Cited by 12
Chung, S., Kim, C.-F., Chow, H., Chong, H.-C., Tam, S.-Y., Leung, Y., & Lo, W. H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207445 · Cited by 12
Peixoto, J., Janaki‐Raman, S., Schlicker, L., Schmitz, W., Walz, S., Winkelkotte, A. M., Herold‐Mende, C. C., Soares, P., Schulze, A., & Lima, J. P. (2021) · Cancers · doi:10.3390/cancers13061327 · Cited by 12
Karabulutoglu, M., Finnon, R., Imaoka, T., Friedl, A. A., & Badie, C. (2018) · International Journal of Radiation Biology · doi:10.1080/09553002.2018.1490042 · Cited by 11
PEGylation increases antitumoral activity of arginine deiminase of Streptococcus pyogenes
Schwarz, R., Zitzow, E., Fiebig, A., Hering, S., Humboldt, Y., Schoenwaelder, N., Kämpfer, N., Volkmar, K., Hinz, B., Kreikemeyer, B., et al. (2021) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-021-11728-7 · Cited by 11
Sun, P., Zhu, X., Shrubsole, M. J., Ness, R. M., Hibler, E. A., Cai, Q., Long, J., Chen, Z., Li, G., Hou, L., et al. (2017) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2017.04.016 · Cited by 11
Metabolic characteristics in hepatocellular carcinoma: amino acid metabolic reprogramming
Zhou, R., Li, Y., Li, G., Li, Y., Luo, L., Wang, B., & Wang, L. (2026) · Molecular Cancer · doi:10.1186/s12943-025-02492-7 · Cited by 11
Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer
Shum, H. C. E., Wu, K., Vadgama, J. V., & Wu, Y. (2023) · Journal of Personalized Medicine · doi:10.3390/jpm13010157 · Cited by 10
Yang, H., Lin, M. T., Xiong, F., Yang, Y. P., Nie, X., & Zhou, R. L. (2009) · Oncology Letters · doi:10.3892/ol_00000005 · Cited by 10
Flavonoids as modulators of metabolic reprogramming in renal cell carcinoma (Review)
Shahzad, A., Liu, W., Sun, Y., Liu, X., Xia, J., Cui, K., Sai, B., Zhu, Y., Yang, Z., & Zhang, Q. (2024) · Oncology Reports · doi:10.3892/or.2024.8826 · Cited by 9
Metabolic plasticity in pancreatic ductal adenocarcinoma progression and response to treatment
Ma, J., Bhardwaj, V., Lobie, P. E., & Pandey, V. (2026) · Molecular Cancer · doi:10.1186/s12943-026-02620-x · Cited by 10
Genetics and Molecular Biology of Mesothelioma
Fennell, D. A. (2011) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-642-10862-4_9 · Cited by 9
Cheng, S. M., Shieh, M., Lin, T., & Cheung, C. H. A. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30555 · Cited by 10
Wu, F. L., Liang, Y.-F., Chang, Y.-C., Yo, H.-H., Wei, M., & Shen, L. (2011) · Journal of Biomedical Science · doi:10.1186/1423-0127-18-25 · Cited by 9
Oxidative Stress and X-ray Exposure Levels-Dependent Survival and Metabolic Changes in Murine HSPCs
Karabulutoglu, M., Finnon, R., Cruz-Garcia, L., Hill, M. A., & Badie, C. (2021) · Antioxidants · doi:10.3390/antiox11010011 · Cited by 9
A Review of Novel Cancer Therapeutics and Current Research Trends
Oluwajembola, A. M., Zakari, S., Cleanclay, W. D., Ayeni, T. O., Adebosoye, A., Okoh, O. S., Folamade, J., Bawa, I., & Ogunlana, O. O. (2025) · The Scientific World JOURNAL · doi:10.1155/tswj/5056618 · Cited by 8
Simultaneous analysis of citrulline and arginine in serum and tissue
Mao, H.-M., Chen, B.-G., Wang, W.-M., Zhuang, P., Zong, M., & Xu, Z. (2010) · Microchemical Journal · doi:10.1016/j.microc.2010.10.001 · Cited by 8
On the metabolic origin of cancer: substances that target tumor metabolism
Israël, M., & Schwartz, L. H. (2011) · Biomedical Research-tokyo · Cited by 8
Human arginase I: a potential broad-spectrum anti-cancer agent
Anakha, J., Prasad, Y. R., Sharma, N., & Pande, A. H. (2023) · 3 Biotech · doi:10.1007/s13205-023-03590-3 · Cited by 9
Prabhu, R. H., Bhise, K., & Patravale, V. B. (2016) · Advances in food and nutrition research · doi:10.1016/bs.afnr.2016.10.001 · Cited by 7
Advances in Drug Therapy for Metastatic Pancreatic Ductal Adenocarcinoma
Gao, J., Wang, J., Guan, C., Shi, W., Dong, Q., Sheng, J., Zou, X., Xu, Z., Ge, Y., Huang, Z., et al. (2024) · Journal of Cancer · doi:10.7150/jca.89788 · Cited by 7
Cancer therapies based on enzymatic amino acid depletion
Teixeira, C. S. S., Fernandes, H. S., Fernandes, P. A., Ramos, M. J., & Cerqueira, N. M. F. S. A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-46144-3.00024-6 · Cited by 6
Li, Z., Zhou, S. Y., Yang, X., Li, X., Yang, G. X., Chant, J., Snyder, M. P., & Wang, X. (2021) · Nutrition and Cancer · doi:10.1080/01635581.2021.2013904 · Cited by 6
Relapsed Synovial Sarcoma: Treatment Options
Weiss, M. C., & Tine, B. A. V. (2023) · Current Treatment Options in Oncology · doi:10.1007/s11864-023-01056-5 · Cited by 6
Hu, X., Jing, F., Wang, Q., Shi, L., Cao, Y., & Zhu, Z. (2021) · ONCOLOGIE · doi:10.32604/oncologie.2021.016155 · Cited by 4
Distinguishing the pros and cons of metabolic reprogramming in oncolytic virus immunotherapy
Wang, S., & Wei, J. (2022) · International Journal of Cancer · doi:10.1002/ijc.34139 · Cited by 3
Metabolic Reprogramming in Cancer
Prusty, D., & Manna, S. K. (2022) · Wiley eBooks · doi:10.1002/9781119851042.ch25 · Cited by 3
Tumor starvation by L-arginine deprivation
Fried, R., Carlton, R. M., & Fried, D. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-824013-7.00005-5 · Cited by 2
Enzymes in oncohematology: relevant directions of experimental studies and prospects of clinical use
Pokrovskiy, V. S., & Трещалина, Е. М. (2014) · Clinical oncohematology · doi:10.21320/2500-2139-2014-7-1-28-38 · Cited by 2
Kassab, M. M. S. (2024) · Research Square · doi:10.21203/rs.3.rs-4126905/v1 · Cited by 2
Arginine Metabolism: An Enlightening Therapeutic Attribute for Cancer Treatment
Narayan, K. S., & Kashyap, R. (2021) · BiblioBoard Library Catalog (Open Research Library) · doi:10.5772/intechopen.97254 · Cited by 1
Bacterial metabolomics: current applications for human welfare and future aspects
Jamal, Q. M. S., & Ahmad, V. (2024) · Journal of Asian Natural Products Research · doi:10.1080/10286020.2024.2385365 · Cited by 1
Precision Approaches to Pancreatic Cancer Therapy: What Now and What Next?
Keane, F., Park, W., & O'Reilly, E. M. (2022) · Current Treatment Options in Gastroenterology · doi:10.1007/s11938-022-00386-x · Cited by 1
Tumor Metabolism: Challenges and Future Perspectives
da Silva, E. L., Montenegro, R. C., & Moreira-Nunes, C. A. (2023) · Springer eBooks · doi:10.1007/978-3-030-80962-1_103-1 · Cited by 3
Arginine Deiminase and Cancer Therapy
Feun, L. G., Kuo, M. T., You, M., Wu, C. J., Wangpaichitr, M., & Savaraj, N. (2010) · doi:10.1002/9780470626528.ch9 · Cited by 1
Ji, J. X. Y., Cochrane, D. R., Tessier‐Cloutier, B., Chen, S. Y., Ho, G., Pathak, K. V., Alcazar, I. N., Farnell, D., Leung, S., Cheng, A. S., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/845586
Kobayashi, E., Masuda, M., Nakayama, R. T., Ichikawa, H., Satow, R., Shitashige, M., Honda, K., Yamaguchi, U., Shoji, A., Tochigi, N., et al. (2023) · doi:10.1158/1535-7163.c.6531447
Kobayashi, E., Masuda, M., Nakayama, R. T., Ichikawa, H., Satow, R., Shitashige, M., Honda, K., Yamaguchi, U., Shoji, A., Tochigi, N., et al. (2023) · doi:10.1158/1535-7163.c.6531447.v1
Metabolic Reprogramming of Clear Cell Renal Cell Carcinoma and Its Clinical Significance
周, 文. (2024) · Advances in Clinical Medicine · doi:10.12677/acm.2024.1451486
Tumor Metabolism: Challenges and Future Perspectives
da Silva, E. L., Montenegro, R. C., & Moreira-Nunes, C. A. (2025) · Springer eBooks · doi:10.1007/978-3-032-00761-2_103
Etude de la reprogrammation métabolique de l' adénocarcinome canalaire pancréatique
Olivares, O. (2015) · theses.fr (ABES) · doi:10.70675/ef2c6a2czab6dz4a68z8004z1ade8605dadc
Camus, M. (2017) · theses.fr (ABES) · doi:10.70675/4def68c4zdc9ez422eza783z692c3f1ea21e
Molins, E. A. G. (2020) · theses.fr (ABES) · doi:10.70675/252d1be2z22e8z4378zb146zfd4ec7fa46a7
The role of L-Arginine metabolism in the hallmarks of cancer as an emerging pathway to drug design
Garcia-Valdez, G., Vazquez-Galvan, A. E., Gonzalez-Llerena, J. L., Treviño-Almaguer, D., Gallegos-Ibarra, D. L., Guajardo-Gonzalez, D., Balderas-Renterı́a, I., Camacho‐Corona, M. D. R., & Espinosa-Rodríguez, B. A. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1851940
L-arginine metabolism in breast cancer: mechanisms and therapeutic targets
Röglin, A., Böger, R. H., & Hannemann, J. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1844871
Mainz, L., Sarhan, M. A. F. E., Schlicker, L., Kirner, S., Morton, J. P., Hartmann, E., Rosenwald, A., Eilers, U., Schuelein‐Voelk, C., Schmitz, W., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.03.740778
Boosting CAR T cell efficacy in cancer with metabolic insights from design to diet
Morgan, J., MacPherson, S., & Lum, J. J. (2026) · Nature reviews. Cancer · doi:10.1038/s41568-026-00984-2
Metadata
- Authors
- Bowles, T. L., Kim, R., Galante, J., Parsons, C. M., Virudachalam, S., Kung, H., & Bold, R. J.
- Affiliations
- University of California Davis Medical Center (US)
- Corresponding author
- Bold, Richard J.
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2008-08-13
- Volume
- 123
- Issue
- 8
- Pages
- 1950-1955
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- PMC
- PMC4294549
- OpenAlex
- W2119097025
- Cited by
- 153
- References
- 44
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 7 · 2023: 13 · 2022: 8 · 2021: 15 · 2020: 9 · 2019: 11 · 2018: 8 · 2017: 11 · 2016: 11 · 2015: 6 · 2014: 14 · 2013: 4 · 2012: 3
- FWCI
- 6.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30CA093373)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK052659)
- 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
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- pancreatic cancer, argininosuccinate synthetase, arginine deprivation, arginine deiminase, arginine auxotrophy, apoptosis, caspase activation, tumor xenografts, arginine metabolism, cancer cell lines
- MeSH terms
- Animals, Arginine, Argininosuccinate Synthase, Humans, Hydrolases, Immunohistochemistry, Mice, Nude, Pancreatic Neoplasms, Polyethylene Glycols, RNA, Messenger, Apoptosis, Xenograft Model Antitumor Assays, Cell Growth Processes, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
