Amino Acid Deprivation Therapy: A Promising Avenue in Cancer Treatment
Abstract
A promising method for treating cancer is amino acid deprivation therapy, which targets the metabolic reliance of cancer cells on particular amino acids. Because of their elevated rates of proliferation and dysregulated metabolic pathways, many cancer cells have a higher need for certain amino acids than normal cells. The therapeutic potential of amino acid deprivation is examined in this paper, with particular attention paid to the depletion of essential amino acids that are essential for the survival and proliferation of cancer cells, such as glutamine, methionine, and arginine. There is discussion of several tactics, such as the use of small-molecule inhibitors, dietary restrictions, and recombinant enzymes (such as arginine deiminase and asparaginase).The study also assesses preclinical and clinical research that shows these methods are safe and effective for various cancer types. Additionally examined are the mechanisms by which amino acid deficiency triggers cell cycle arrest, autophagy, and apoptosis. Potential combinatorial techniques to improve therapeutic efficacy are discussed, along with difficulties relating to toxicity and resistance mechanisms. Future directions in amino acid deprivation therapy are highlighted in the review's conclusion, with a focus on the necessity of individualized strategies catered to each tumors unique metabolic weakness.
Keywords:
Arginine deiminase, Cancer therapy, Amino acid deprivation, Enzyme inhibition, Amino acid and cancerDOI
https://doi.org/10.22376/ijpbs.v16i4.160References
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi:10.3322/caac.21492
2. Park JG, Tak WY, Park SY, Kweon YO, Chung WJ, Jang BK, et al. Effects of branched-chain amino acid (BCAA) supplementation on the progression of advanced liver disease: A Korean nationwide, multicenter, prospective, observational, cohort study. Nutrients. 2020;12(5):1429. doi:10.3390/nu12051429.
3. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA A Cancer J Clinicians. 2023 Jan;73(1):17–48.
4. Longley D, Johnston P. Molecular mechanisms of drug resistance. The Journal of Pathology. 2005 Jan;205(2):275–92.
5. Baskar R, Dai J, Wenlong N, Yeo R, Yeoh KW. Biological response of cancer cells to radiation treatment. Front Mol Biosci [Internet]. 2014 Nov 17 [cited 2025 Nov 28];1. Available from: http://journal.frontiersin.org/article/10.3389/fmolb.2014.00024/abstract
6. Zhang H, Chen J. Current status and future directions of cancer immunotherapy. J Cancer. 2018;9(10):1773–81.
7. Garraway LA, Jänne PA. Circumventing Cancer Drug Resistance in the Era of Personalized Medicine. Cancer Discovery. 2012 Mar 1;2(3):214–26.
8. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018 Apr 12;378(15):1408–18.
9. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. The Lancet. 2009 May;373(9674):1550–61.
10. Dienstmann R, Rodon J, Barretina J, Tabernero J. Genomic Medicine Frontier in Human Solid Tumors: Prospects and Challenges. JCO. 2013 May 20;31(15):1874–84.
11. DeBerardinis RJ, Cheng T. Q’s next: The diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29(3):313-24. doi:10.1038/onc.2009.358
12. Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, et al. Metabolic heterogeneity in human lung tumors. Cell. 2016;164(4):681-94. doi:10.1016/j.cell.2015.12.034
13. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011;43(9):869-74. doi:10.1038/ng.890
14. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960-76. doi:10.1016/j.cell.2017.02.004
15. Pavlova NN, Thompson CB. The emerging hallmarks of cancer metabolism. Cell Metab. 2016;23(1):27–47. doi:10.1016/j.cmet.2015.12.006.
16. Tarne P, Traverso M, Finkbeiner M. Review of life cycle sustainability assessment and potential for its adoption at an automotive company. Sustainability. 2017;9(4):670. doi:10.3390/su9040670.
17. Forstermann U, Sessa WC. Nitric oxide synthases: Regulation and function. Eur Heart J. 2012;33(7):829–37. doi:10.1093/eurheartj/ehr304.
18. Scalise M, Console L, Cosco J, Pochini L, Galluccio M, Indiveri C. ASCT1 and ASCT2: Brother and sister? SLAS Discov. 2021;26(9):1148–63. doi:10.1177/24725552211030288.
19. Bhutia YD, Babu E, Ramachandran S, Ganapathy V. Amino acid transporters in cancer and their relevance to “glutamine addiction”: Novel targets for the design of a new class of anticancer drugs. Cancer Res. 2015;75(9):1782–8. doi:10.1158/0008-5472.CAN-14-3745.
20. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.
21. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 2009;136(3):521–34. doi:10.1016/j.cell.2008.11.044.
22. Sousa CM, Kimmelman AC. The complex landscape of pancreatic cancer metabolism. Carcinogenesis. 2014;35(7):1441–50. doi:10.1093/carcin/bgu097.
23. Hensley CT, Wasti AT, DeBerardinis RJ. Glutamine and cancer: Cell biology, physiology, and clinical opportunities. J Clin Invest. 2013;123(9):3678–84. doi:10.1172/JCI69600.
24. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol. 2014;61(3):642–59. doi:10.1016/j.jhep.2014.05.042.
25. Hayaishi S, Chung H, Kudo M, Ishikawa E, Takita M, Ueda T, et al. Oral branched-chain amino acid granules reduce the incidence of hepatocellular carcinoma and improve event-free survival in patients with liver cirrhosis. Dig Dis. 2011;29(3):326–32. doi:10.1159/000327571.
26. Poon RTP, Yu WC, Fan ST, Wong J. Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: A randomized trial. Aliment Pharmacol Ther. 2004;19(7):779–88. doi:10.1111/j.1365-2036.2004.01920.x.
27. Park JG, Tak WY, Park SY, Kweon YO, Chung WJ, Jang BK, et al. Effects of branched-chain amino acid (BCAA) supplementation on the progression of advanced liver disease: A Korean nationwide, multicenter, prospective, observational, cohort study. Nutrients. 2020;12(5):1429. doi:10.3390/nu12051429.
28. Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: A double-blind, randomized trial. Gastroenterology. 2003;124(7):1792–801. doi:10.1016/S0016-5085(03)00323-8.
29. Ishak Gabra MB, Yang Y, Lowman XH, Reid MA, Tran TQ, Kong M. IKKβ activates p53 to promote cancer cell adaptation to glutamine deprivation. Oncogenesis. 2018;7(11):93. doi:10.1038/s41389-018-0104-0.
30. Kanarek N, Keys HR, Cantor JR, Lewis CA, Chan SH, Kunchok T, et al. Histidine catabolism is a major determinant of methotrexate sensitivity. Nature. 2018;559(7715):632–6. doi:10.1038/s41586-018-0316-7.
31. Ragni M, Ruocco C, Tedesco L, Carruba MO, Valerio A, Nisoli E. An amino acid-defined diet impairs tumour growth in mice by promoting endoplasmic reticulum stress and mTOR inhibition. Mol Metab. 2022;60:101478. doi:10.1016/j.molmet.2022.101478.
32. Wang Z, Xie Q, Zhou H, Zhang M, Shen J, Ju D. Amino acid degrading enzymes and autophagy in cancer therapy. Front Pharmacol. 2021;11:582587. doi:10.3389/fphar.2020.582587.
33. Juluri KR, Siu C, Cassaday RD. Asparaginase in the treatment of acute lymphoblastic leukemia in adults: Current evidence and place in therapy. Blood Lymphat Cancer. 2022;12:55–79. doi:10.2147/BLCTT.S342052.
34. Galluzzi L, Kepp O, Van Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat Rev Drug Discov. 2013;12(11):829–46. doi:10.1038/nrd4145.
35. Lomelino CL, Andring JT, McKenna R, Kilberg MS. Asparagine synthetase: Function, structure, and role in disease. J Biol Chem. 2017;292(49):19952–8. doi:10.1074/jbc.R117.819060.
36. Maita T, Matsuda G. The primary structure of L-asparaginase from Escherichia coli. Hoppe Seyler’s Z Physiol Chem. 1980;361(1):105–18. doi:10.1515/bchm2.1980.361.1.105.
37. Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: Pegaspargase (Oncaspar®) for the first-line treatment of children with acute lymphoblastic leukemia (ALL). Oncologist. 2007;12(8):991–8. doi:10.1634/theoncologist.12-8-991.
38. Chan WK, Horvath TD, Tan L, Link T, Harutyunyan KG, Pontikos MA, et al. Glutaminase activity of L-asparaginase contributes to durable preclinical activity against acute lymphoblastic leukemia. Mol Cancer Ther. 2019;18(9):1587–92. doi:10.1158/1535-7163.MCT-18-1329.
39. Tardito S, Uggeri J, Bozzetti C, Bianchi MG, Rotoli BM, Franchi-Gazzola R, et al. The inhibition of glutamine synthetase sensitizes human sarcoma cells to L-asparaginase. Cancer Chemother Pharmacol. 2007;60(5):751–8. doi:10.1007/s00280-007-0421-z.
40. Davis CD, Uthus EO. DNA methylation, cancer susceptibility, and nutrient interactions. Exp Biol Med. 2004;229(10):988–95. doi:10.1177/153537020422901002.
41. Hermanova I, Arruabarrena-Aristorena A, Valis K, Nuskova H, Alberich-Jorda M, Fiser K, et al. Pharmacological inhibition of fatty-acid oxidation synergistically enhances the effect of L-asparaginase in childhood ALL cells. Leukemia. 2016;30(1):209–18.
42. Covini D, Tardito S, Bussolati O, Chiarelli LR, Pasquetto MV, Digilio R, et al. Expanding targets for a metabolic therapy of cancer: L-asparaginase. Recent Pat Anticancer Drug Discov. 2012;7(1):4–13. doi:10.2174/157489212798358001.
43. Ortega JA, Nesbit ME, Donaldson MH, Hittle RE, Weiner J, Karon M, et al. L-asparaginase, vincristine, and prednisone for induction of first remission in acute lymphocytic leukemia. Cancer Res. 1977;37(2):535–40.
44. Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: Where are we going and how do we get there? Blood. 2012;120(6):1165–74. doi:10.1182/blood-2012-05-378943.
45. Egler RA, Ahuja SP, Matloub Y. L-asparaginase in the treatment of patients with acute lymphoblastic leukemia. J Pharmacol Pharmacother. 2016;7(2):62–71. doi:10.4103/0976-500X.184769.
46. Patel N, Krishnan S, Offman MN, Krol M, Moss CX, Leighton C, et al. A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase. J Clin Invest. 2009;119:37977. doi:10.1172/JCI37977.
47. Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, et al. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol-conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: A Children’s Cancer Group study. Blood. 2002;99(6):1986–94. doi:10.1182/blood.V99.6.1986.
48. Gutierrez JA, Pan YX, Koroniak L, Hiratake J, Kilberg MS, Richards NGJ. An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line. Chem Biol. 2006;13(12):1339–47. doi:10.1016/j.chembiol.2006.10.010.
49. Vélez J, Hail N Jr, Konopleva M, Zeng Z, Kojima K, Samudio I, et al. Mitochondrial uncoupling and the reprogramming of intermediary metabolism in leukemia cells. Front Oncol. 2013;3:67. doi:10.3389/fonc.2013.00067.
50. Kumar S, Venkata Dasu V, Pakshirajan K. Purification and characterization of glutaminase-free L-asparaginase from Pectobacterium carotovorum MTCC 1428. Bioresour Technol. 2011;102(2):2077–82. doi:10.1016/j.biortech.2010.07.114.
51. Offman MN, Krol M, Patel N, Krishnan S, Liu J, Saha V, et al. Rational engineering of L-asparaginase reveals importance of dual activity for cancer cell toxicity. Blood. 2011;117(5):1614–21. doi:10.1182/blood-2010-07-298422.
52. Tan YQ, Loh C-K, Makpol S. A review of L-asparaginase hypersensitivity in paediatric acute lymphoblastic leukaemia patients with regard to the measurement of anti-asparaginase antibodies and their genetic predisposition. Malays J Med Sci. 2023;30(5):40–51. doi:10.21315/mjms2023.30.5.4.
53. Pieters R, Hunger SP, Boos J, Rizzari C, Silverman L, Baruchel A, et al. L-asparaginase treatment in acute lymphoblastic leukemia: A focus on Erwinia asparaginase. Cancer. 2011;117(2):238–49. doi:10.1002/cncr.25489.
54. Kurtzberg J, Asselin B, Bernstein M, Buchanan GR, Pollock BH, Camitta BM. Polyethylene glycol-conjugated L-asparaginase versus native L-asparaginase in combination with standard agents for children with acute lymphoblastic leukemia in second bone marrow relapse: A Children’s Oncology Group Study (POG 8866). J Pediatr Hematol Oncol. 2011;33(8):610–6. doi:10.1097/MPH.0b013e31822d4d4e.
55. Wang B, Relling MV, Storm MC, Woo MH, Ribeiro R, Pui C-H, et al. Evaluation of immunologic cross reaction of anti-asparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients. Leukemia. 2003;17(8):1583–8. doi:10.1038/sj.leu.2403011.
56. Tsegaye K, Tsehai BA, Getie B. Desirable L-asparaginases for treating cancer and current research trends. Front Microbiol. 2024;15:1269282. doi:10.3389/fmicb.2024.1269282.
57. Sharma B, Singh S, Kanwar SS. L-methionase: A therapeutic enzyme to treat malignancies. Biomed Res Int. 2014;2014:1–13. doi:10.1155/2014/506287.
58. Lockwood BC, Coombs GH. Purification and characterization of methionine γ-lyase from Trichomonas vaginalis. Biochem J. 1991;279(3):675–82. doi:10.1042/bj2790675.
59. Nakayama T, Esaki N, Sugie K, Beresov TT, Tanaka H, Soda K. Purification of bacterial L-methionine γ-lyase. Anal Biochem. 1984;138(2):421–4. doi:10.1016/0003-2697(84)90832-7.
60. Amyes TL, Richard JP. Enzymatic catalysis of proton transfer at carbon: Activation of triosephosphate isomerase by phosphite dianion. Biochemistry. 2007;46(19):5841–54. doi:10.1021/bi700409b.
61. Lauinger L, Kaiser P. Sensing and signaling of methionine metabolism. Metabolites. 2021;11(2):83. doi:10.3390/metabo11020083.
62. Kaiser P. Methionine dependence of cancer. Biomolecules. 2020;10(4):568. doi:10.3390/biom10040568.
63. Bandaru N, Noor SM, Kammili ML, Bonthu MG, Gayatri AP, Kumar PK. Methionine restriction for cancer therapy: From preclinical studies to clinical trials. Cancer Pathog Ther. 2025;S2949713225000023. doi:10.1016/j.cpt.2025.01.002.
64. Swisher EM, Gonzalez RM, Taniguchi T, Garcia RL, Walsh T, Goff BA, et al. Methylation and protein expression of DNA repair genes: Association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas. Mol Cancer. 2009;8:48. doi:10.1186/1476-4598-8-48.
65. Geiman TM, Muegge K. DNA methylation in early development. Mol Reprod Dev. 2010;77(2):105–13. doi:10.1002/mrd.21118.
66. Espe M, Adam AC, Saito T, Skjærven KH. Methionine: An indispensable amino acid in cellular metabolism and health of Atlantic salmon. Aquac Nutr. 2023;2023:1–10. doi:10.1155/2023/5706177.
67. Sharma B, Singh S, Kanwar SS. L-methionase: A therapeutic enzyme to treat malignancies. Biomed Res Int. 2014;2014:1–13. doi:10.1155/2014/506287.
68. Alami N, Page V, Yu Q, Jerome L, Paterson J, Shiry L, et al. Recombinant human insulin-like growth factor-binding protein 3 inhibits tumor growth and targets the Akt pathway in lung and colon cancer models. Growth Horm IGF Res. 2008;18(6):487–96. doi:10.1016/j.ghir.2008.04.002.
69. Miki K, Xu M, Gupta A, Ba Y, Tan Y, Al-Refaie W, et al. Methioninase cancer gene therapy with selenomethionine as suicide prodrug substrate. Cancer Res. 2001;61(18):6805–10.
70. Keshtkar S, Kaviani M, Soleimanian S, Azarpira N, Asvar Z, Pakbaz S. Stem cell-derived exosome as potential therapeutics for microbial diseases. Front Microbiol. 2021;12:786111. doi:10.3389/fmicb.2021.786111.
71. Zeng H, Wu M, Botnen JH. Methylselenol, a selenium metabolite, induces cell cycle arrest in G1 phase and apoptosis via the extracellular-regulated kinase 1/2 pathway and other cancer signaling genes. J Nutr. 2009;139(9):1613–8. doi:10.3945/jn.109.110320.
72. Cabral-Pacheco GA, Garza-Veloz I, Castruita-De La Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, et al. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci. 2020;21(24):9739. doi:10.3390/ijms21249739.
73. Zeng H, Wu M, Botnen JH. Methylselenol, a selenium metabolite, induces cell cycle arrest in G1 phase and apoptosis via the extracellular-regulated kinase 1/2 pathway and other cancer signaling genes. J Nutr. 2009;139(9):1613–8. doi:10.3945/jn.109.110320.
74. Cho SD, Jiang C, Malewicz B, et al. Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgen-stimulated transcription. Mol Cancer Ther. 2004;3(5):605–11.
75. Jena AB, Samal RR, Bhol NK, Duttaroy AK. Cellular Red-Ox system in health and disease: The latest update. Biomed Pharmacother. 2023;162:114606. doi:10.1016/j.biopha.2023.114606.
76. Fernandes AP, Wallenberg M, Gandin V, Misra S, Tisato F, Marzano C, et al. Methylselenol formed by spontaneous methylation of selenide is a superior selenium substrate to the thioredoxin and glutaredoxin systems. PLoS One. 2012;7(11):e50727. doi:10.1371/journal.pone.0050727.
77. Schrauzer GN. Selenomethionine: A review of its nutritional significance, metabolism and toxicity. J Nutr. 2000;130(7):1653–6. doi:10.1093/jn/130.7.1653.
78. Morozova EA, Anufrieva NV, Davydov DZh, Komarova MV, Dyakov IN, Rodionov AN, et al. Plasma methionine depletion and pharmacokinetic properties in mice of methionine γ-lyase from Citrobacter freundii, Clostridium tetani and Clostridium sporogenes. Biomed Pharmacother. 2017;88:978–84. doi:10.1016/j.biopha.2017.01.127.
79. Courtney ME, Greene HL, Folk CC, Helinek GL, Dmitruk A. Rapidly declining serum albumin values in newly hospitalized patients: Prevalence, severity, and contributory factors. J Parenter Enteral Nutr. 1982;6(2):143–5. doi:10.1177/0148607182006002143.
80. Sun X, Yang Z, Li S, et al. In vivo efficacy of recombinant methioninase is enhanced by the combination of polyethylene glycol conjugation and pyridoxal 5'-phosphate supplementation. Cancer Res. 2003;63(23):8377–83.
81. Sato D, Nozaki T. Methionine gamma-lyase: The unique reaction mechanism, physiological roles, and therapeutic applications against infectious diseases and cancers. IUBMB Life. 2009;61(11):1019–28. doi:10.1002/iub.255.
82. Couchet M, Breuillard C, Corne C, Rendu J, Morio B, Schlattner U, et al. Ornithine transcarbamylase – From structure to metabolism: An update. Front Physiol. 2021;12:748249. doi:10.3389/fphys.2021.748249.
83. Patange S, Ball DA, Wan Y, Karpova TS, Girvan M, Levens D, et al. MYC amplifies gene expression through global changes in transcription factor dynamics. Cell Rep. 2022;38(4):110292. doi:10.1016/j.celrep.2021.110292.
84. Yoo HC, Yu YC, Sung Y, Han JM. Glutamine reliance in cell metabolism. Exp Mol Med. 2020;52(9):1496–516. doi:10.1038/s12276-020-00504-8.
85. Wu G, Bazer FW, Davis TA, Kim SW, Li P, Rhoads MR, et al. Arginine metabolism and nutrition in growth, health and disease. Amino Acids. 2009;37(1):153–68. doi:10.1007/s00726-008-0210-y.
86. Haines RJ, Pendleton LC, Eichler DC. Argininosuccinate synthase: At the center of arginine metabolism. Int J Biochem Mol Biol. 2011;2(1):8–23.
87. Husson A, Brasse-Lagnel C, Fairand A, Renouf S, Lavoinne A. Argininosuccinate synthetase from the urea cycle to the citrulline–NO cycle. Eur J Biochem. 2003;270(9):1887–99. doi:10.1046/j.1432-1033.2003.03559.x.
88. Bobak YP, Vynnytska BO, Kurlishchuk YV, Sibirny AA, Stasyk OV. Cancer cell sensitivity to arginine deprivation in vitro is not determined by endogenous levels of arginine metabolic enzymes. Cell Biol Int. 2010;34(11):1085–9. doi:10.1042/CBI20100451.
89. Chen C-L, Hsu S-C, Ann DK, Yen Y, Kung H-J. Arginine signaling and cancer metabolism. Cancers. 2021;13(14):3541. doi:10.3390/cancers13143541.
90. Buel GR, Dang HQ, Asara JM, Blenis J, Mutvei AP. Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1. J Biol Chem. 2022;298(6):102030. doi:10.1016/j.jbc.2022.102030.
91. Sahu D, Gupta S, Hau AM, Nakashima K, Leivo MZ, Searles SC, et al. Argininosuccinate synthetase 1 loss in invasive bladder cancer regulates survival through general control nonderepressible 2 kinase–mediated eukaryotic initiation factor 2α activity and is targetable by pegylated arginine deiminase. Am J Pathol. 2017;187(1):200–13. doi:10.1016/j.ajpath.2016.09.004.
92. Endicott M, Jones M, Hull J. Amino acid metabolism as a therapeutic target in cancer: A review. Amino Acids. 2021;53(8):1169–79. doi:10.1007/s00726-021-03052-1.
93. Roeksomtawin S, Navasumrit P, Waraprasit S, Parnlob V, Sricharunrat T, Bhudhisawasdi V, et al. Decreased argininosuccinate synthetase expression in Thai patients with cholangiocarcinoma and the effects of ADI PEG20 treatment in CCA cell lines. Oncol Lett. 2018. doi:10.3892/ol.2018.8807.
94. Huang W-H, Chang M-C, Tsai K-S, Hung M-C, Chen H-L, Hung S-C. Mesenchymal stem cells promote growth and angiogenesis of tumors in mice. Oncogene. 2013;32(37):4343–52. doi:10.1038/onc.2012.458.
95. Delage B, Luong P, Maharaj L, O’Riain C, Syed N, Crook T, et al. Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis. 2012;3(7):e342. doi:10.1038/cddis.2012.83.
96. Sun N, Zhao X. Argininosuccinate synthase 1, arginine deprivation therapy and cancer management. Front Pharmacol. 2022;13:935553. doi:10.3389/fphar.2022.935553.
97. Phillips MM, Sheaff MT, Szlosarek PW. Targeting arginine-dependent cancers with arginine-degrading enzymes: Opportunities and challenges. Cancer Res Treat. 2013;45(4):251–62. doi:10.4143/crt.2013.45.4.251.
98. Huang H-Y, Wu W-R, Wang Y-H, Wang J-W, Fang F-M, Tsai J-W, et al. ASS1 as a Novel Tumor Suppressor Gene in Myxofibrosarcomas: Aberrant Loss via Epigenetic DNA Methylation Confers Aggressive Phenotypes, Negative Prognostic Impact, and Therapeutic Relevance. Clin Cancer Res. 2013;19(11):2861–72. doi:10.1158/1078-0432.CCR-12-2641.
99. Cheon D-J, Tong Y, Sim M-S, Dering J, Berel D, Cui X, et al. A Collagen-Remodeling Gene Signature Regulated by TGF-β Signaling Is Associated with Metastasis and Poor Survival in Serous Ovarian Cancer. Clin Cancer Res. 2014;20(3):711–23. doi:10.1158/1078-0432.CCR-13-1256.
100. Singh PK, Deorukhkar AA, Venkatesulu BP, Li X, Tailor R, Bomalaski JS, et al. Exploiting Arginine Auxotrophy with Pegylated Arginine Deiminase (ADI-PEG20) to Sensitize Pancreatic Cancer to Radiotherapy via Metabolic Dysregulation. Mol Cancer Ther. 2019;18(12):2381–93. doi:10.1158/1535-7163.MCT-18-0708.
101. Kim RH, Coates JM, Bowles TL, McNerney GP, Sutcliffe J, Jung JU, et al. Arginine Deiminase as a Novel Therapy for Prostate Cancer Induces Autophagy and Caspase-Independent Apoptosis. Cancer Res. 2009;69(2):700–8. doi:10.1158/0008-5472.CAN-08-3157.
102. Changou CA, Chen Y-R, Xing L, Yen Y, Chuang FYS, Cheng RH, et al. Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy. Proc Natl Acad Sci U S A. 2014;111(39):14147–52. doi:10.1073/pnas.1404171111.
103. Zeng H, Wu M, Botnen JH. Methylselenol, a Selenium Metabolite, Induces Cell Cycle Arrest in G1 Phase and Apoptosis via the Extracellular-Regulated Kinase 1/2 Pathway and Other Cancer Signaling Genes. J Nutr. 2009;139(9):1613–8. doi:10.3945/jn.109.110320.
104. Chalishazar MD, Wait SJ, Huang F, Ireland AS, Mukhopadhyay A, Lee Y, et al. MYC-Driven Small-Cell Lung Cancer is Metabolically Distinct and Vulnerable to Arginine Depletion. Clin Cancer Res. 2019;25(16):5107–21. doi:10.1158/1078-0432.CCR-18-4140.
105. Kelly MP, Jungbluth AA, Wu B-W, Bomalaski J, Old LJ, Ritter G. Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase. Br J Cancer. 2012;106(2):324–32. doi:10.1038/bjc.2011.524.
106. Bean GR, Kremer JC, Prudner BC, Schenone AD, Yao J-C, Schultze MB, et al. A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas. Cell Death Dis. 2016;7(10):e2406. doi:10.1038/cddis.2016.232.
107. Yeon A, You S, Kim M, Gupta A, Park MH, Weisenberger DJ, et al. Rewiring of cisplatin-resistant bladder cancer cells through epigenetic regulation of genes involved in amino acid metabolism. Theranostics. 2018;8(16):4520–34. doi:10.7150/thno.25130.
108. McAlpine JA, Lu H-T, Wu KC, Knowles SK, Thomson JA. Down-regulation of argininosuccinate synthetase is associated with cisplatin resistance in hepatocellular carcinoma cell lines: Implications for PEGylated arginine deiminase combination therapy. BMC Cancer. 2014;14:621. doi:10.1186/1471-2407-14-621.
109. Savaraj N, Wu C, Li Y-Y, Wangpaichitr M, You M, Bomalaski J, et al. Targeting argininosuccinate synthetase negative melanomas using combination of arginine degrading enzyme and cisplatin. Oncotarget. 2015;6(8):6295–309. doi:10.18632/oncotarget.3370.
110. Prudner BC, Rathore R, Robinson AM, Godec A, Chang SF, Hawkins WG, et al. Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors. Clin Cancer Res. 2019;25(16):5122–34. doi:10.1158/1078-0432.CCR-19-0206.
111. Thongkum A, Wu C, Li Y-Y, Wangpaichitr M, Navasumrit P, Parnlob V, et al. The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma. Int J Mol Sci. 2017;18(6):1175. doi:10.3390/ijms18061175.
112. Daylami R, Muilenburg DJ, Virudachalam S, Bold RJ. Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer. J Exp Clin Cancer Res. 2014;33:102. doi:10.1186/s13046-014-0102-9.
113. Alexandrou C, Al-Aqbi SS, Higgins JA, Boyle W, Karmokar A, Andreadi C, et al. Sensitivity of Colorectal Cancer to Arginine Deprivation Therapy is Shaped by Differential Expression of Urea Cycle Enzymes. Sci Rep. 2018;8(1):12096. doi:10.1038/s41598-018-30591-7.
114. Przystal JM, Hajji N, Khozoie C, Renziehausen A, Zeng Q, Abaitua F, et al. Efficacy of arginine depletion by ADI-PEG20 in an intracranial model of GBM. Cell Death Dis. 2018;9:1192. doi:10.1038/s41419-018-1195-4.
115. Hodakoski C, Hopkins BD, Zhang G, Su T, Cheng Z, Morris R, et al. Rac-Mediated Macropinocytosis of Extracellular Protein Promotes Glucose Independence in Non-Small Cell Lung Cancer. Cancers. 2019;11(1):37. doi:10.3390/cancers11010037.
116. Kumar R, Mishra A, Gautam P, Feroz Z, Vijayaraghavalu S, Likos E, et al. Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy. Cancers. 2022;14(21):5268. doi:10.3390/cancers14215268.
117. Qian K, Zhong S, Xie K, Yu D, Yang R, Gong D. Hepatic ALT isoenzymes are elevated in gluconeogenic conditions including diabetes and suppressed by insulin at the protein level. Diabetes Metab Res Rev. 2015;31(6):562–71. doi:10.1002/dmrr.2655.
118. Yang M, Vousden KH. Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016;16(10):650–62. doi:10.1038/nrc.2016.81.
119. Ascenção K, Szabo C. Emerging roles of cystathionine β-synthase in various forms of cancer. Redox Biol. 2022;53:102331. doi:10.1016/j.redox.2022.102331.
120. Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza AL, et al. Metabolite Profiling Identifies a Key Role for Glycine in Rapid Cancer Cell Proliferation. Science. 2012;336(6084):1040–4. doi:10.1126/science.1218595.
121. Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP. Erratum: Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol. 2017;14(2):113. doi:10.1038/nrclinonc.2017.1.
122. Cluntun AA, Lukey MJ, Cerione RA, Locasale JW. Glutamine Metabolism in Cancer: Understanding the Heterogeneity. Trends Cancer. 2017;3(3):169–80. doi:10.1016/j.trecan.2017.01.005.
123. Tardito S, Uggeri J, Bozzetti C, Bianchi MG, Rotoli BM, Franchi-Gazzola R, et al. The inhibition of glutamine synthetase sensitizes human sarcoma cells to l-asparaginase. Cancer Chemother Pharmacol. 2007;60(5):751–8. doi:10.1007/s00280-007-0421-z.
124. Choi Y-K, Park K-G. Targeting Glutamine Metabolism for Cancer Treatment. Biomol Ther. 2018;26(1):19–28. doi:10.4062/biomolther.2017.178.
125. Burger JA, Wiestner A. Targeting B cell receptor signalling in cancer: Preclinical and clinical advances. Nat Rev Cancer. 2018;18(3):148–67. doi:10.1038/nrc.2017.121.
126. Choi Y-K, Park K-G. Targeting Glutamine Metabolism for Cancer Treatment. Biomol Ther. 2018;26(1):19–28. doi:10.4062/biomolther.2017.178.
127. Chavez KJ, Garimella SV, Lipkowitz S. Triple negative breast cancer cell lines: One tool in the search for better treatment of triple negative breast cancer. Breast Dis. 2011;32(1–2):35–48. doi:10.3233/BD-2010-0307.
128. Lee CH, Motzer R, Emamekhoo H, Matrana M, Percent I, Hsieh JJ, et al. Telaglenastat plus everolimus in advanced renal cell carcinoma: a randomized, double-blinded, placebo-controlled, phase II ENTRATA trial. Clin Cancer Res. 2022;28(15):3248–55. doi:10.1158/1078-0432.CCR-22-0061.
129. Meric-Bernstam F, Tannir NM, Iliopoulos O, Lee RJ, Telli ML, Fan AC, et al. Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial. Clin Cancer Res. 2022;28(8):1540–8. doi:10.1158/1078-0432.CCR-21-2972.
130. Motzer RJ, Lee C-H, Emamekhoo H, Matrana M, Percent I, Hsieh JJ, et al. ENTRATA: Randomized, double-blind, phase II study of telaglenastat (tela; CB-839) + everolimus (E) vs placebo (pbo) + E in patients (pts) with advanced/metastatic renal cell carcinoma (mRCC). Ann Oncol. 2019;30:v889–v890. doi:10.1093/annonc/mdz394.048.
131. Oliver DK M, Athineos D, Cheung EC, Lee P, Zhang T, Van Den Broek NJF, et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature. 2017;544(7650):372–6. doi:10.1038/nature22056.
132. Freudenberg A, Petzke KJ, Klaus S. Comparison of high-protein diets and leucine supplementation in the prevention of metabolic syndrome and related disorders in mice. J Nutr Biochem. 2012;23(11):1524–30. doi:10.1016/j.jnutbio.2011.10.005.
133. Poff AM, Ari C, Seyfried TN, D’Agostino DP. The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer. PLoS One. 2013;8(6):e65522. doi:10.1371/journal.pone.0065522.
134. Komninou D, Leutzinger Y, Reddy BS, Richie Jr JP. Methionine Restriction Inhibits Colon Carcinogenesis. Nutr Cancer. 2006;54(2):202–8. doi:10.1207/s15327914nc5402_6.
135. Hammoudi N, Riaz Ahmed KB, Garcia-Prieto C, Huang P. Metabolic alterations in cancer cells and therapeutic implications. Chin J Cancer. 2011;30(8):508–25. doi:10.5732/cjc.011.10267.
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