{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T11:06:54Z","timestamp":1783163214113,"version":"3.54.6"},"reference-count":95,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,17]],"date-time":"2018-11-17T00:00:00Z","timestamp":1542412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Energy production is the main task of the cancer cell metabolism because the costs of duplicating are enormous. Although energy is derived in cells by dismantling the carbon-to-carbon bonds of any macronutrient, cancer nutritional needs for energetic purposes have been studied primarily as being dependent on glycolysis. Since the end of the last century, the awareness of the dependence of cancer metabolism on amino acids not only for protein synthesis but also to match energy needs has grown. The roles of specific amino acids such as glutamine, glycine and serine have been explored in different experimental conditions and reviewed. Moreover, epidemiological evidence has revealed that some amino acids used as a supplement for therapeutic reasons, particularly the branched-chain ones, may reduce the incidence of liver cancer and a specific molecular mechanism has been proposed as functional to their protective action. By contrast and puzzling clinicians, the metabolomic signature of some pathologies connected to an increased risk of cancer, such as prolonged hyperinsulinemia in insulin-resistant patients, is identified by elevated plasma levels of the same branched-chain amino acids. Most recently, certain formulations of amino acids, deeply different from the amino acid compositions normally present in foods, have shown the power to master cancer cells epigenetically, slowing growth or driving cancer cells to apoptotic death, while being both beneficial for normal cell function and the animal\u2019s health and lifespan. In this review, we will analyze and try to disentangle some of the many knots dealing with the complexities of amino acid biology and links to cancer metabolism.<\/jats:p>","DOI":"10.3390\/ijms19113631","type":"journal-article","created":{"date-parts":[[2018,11,21]],"date-time":"2018-11-21T11:23:27Z","timestamp":1542799407000},"page":"3631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Is the Response of Tumours Dependent on the Dietary Input of Some Amino Acids or Ratios among Essential and Non-Essential Amino Acids? All That Glitters Is Not Gold"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0445-3106","authenticated-orcid":false,"given":"Francesco S.","family":"Dioguardi","sequence":"first","affiliation":[{"name":"Determinants of Metabolism Research Laboratory, 20137 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1014-297X","authenticated-orcid":false,"given":"Vincenzo","family":"Flati","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied Clinical Sciences, University of L\u2019Aquila, 67100 L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0326-0644","authenticated-orcid":false,"given":"Giovanni","family":"Corsetti","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa, 11-25124 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evasio","family":"Pasini","sequence":"additional","affiliation":[{"name":"Istituti Clinici Scientifici Maugeri IRCCS, Cardiac Rehabilitation of the Institute of Lumezzane (Brescia), 25065 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa, 11-25124 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrc3038","article-title":"Otto Warburg\u2019s contributions to current concepts of cancer metabolism","volume":"11","author":"Koppenol","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.bbrc.2003.11.136","article-title":"Cancer metabolism: Facts, fantasy, and fiction","volume":"313","author":"Zu","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1007\/s11306-014-0760-9","article-title":"The Warburg effect: A balance of flux analysis","volume":"11","author":"Vaitheesvaran","year":"2015","journal-title":"Metabolomics"},{"key":"ref_4","first-page":"1298","article-title":"Bridging food webs, ecosystem metabolism, and biogeochemistry using ecological stoichiometry theory","volume":"12","author":"Elti","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"90","DOI":"10.3389\/fendo.2012.00090","article-title":"The role of head and neck squamous cell carcinoma cancer stem cells in tumorigenesis, metastasis, and treatment failure","volume":"3","author":"Chinn","year":"2012","journal-title":"Front. Endocrin."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Barton, M.D., Delneri, D., Oliver, S.G., Rattray, M., and Bergman, C.M. (2010). Evolutionary Systems Biology of Amino Acid Biosynthetic Cost in Yeast. PLoS ONE, 5.","DOI":"10.1371\/annotation\/b60feca4-9a4f-4311-8a07-4bf16a2f9316"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.15252\/embj.201696151","article-title":"Cancer cell metabolism: The essential role of the non-essential amino acid, glutamine","volume":"36","author":"Zhang","year":"2017","journal-title":"EMBO J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.3892\/mmr.2017.6265","article-title":"Insulin-like growth factor 1 receptor-mediated cell survival in hypoxia depends on the promotion of autophagy via suppression of the PI3K\/Akt\/mTOR signaling pathway","volume":"15","author":"Liu","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jbior.2016.12.001","article-title":"Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects","volume":"64","author":"Amin","year":"2017","journal-title":"Adv. Biol. Reg."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Madiraju, A.K., Alves, T., Zhao, X., Cline, G.W., Zhang, D., Bhanot, S., Samuel, V.T., Kibbey, R.G., and Shulman, G.I. (2016). Arginino succinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism. Proc. Natl. Acad. Sci. USA.","DOI":"10.1073\/pnas.1606022113"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/jnci\/djp034","article-title":"Targeting mTOR: Something old, something new","volume":"101","author":"Gerber","year":"2009","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E354","DOI":"10.1016\/S1470-2045(17)30346-7","article-title":"Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer","volume":"18","author":"Carvalho","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Pulvers, J.N., and Marx, G. (2017). Factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy: A systematic review. Asia-Pac. J. Clin. Oncol.","DOI":"10.1111\/ajco.12694"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Macarulla, T., Fern\u00e1ndez, T., Gallardo, M.E., Hernando, O., L\u00f3pez, A.M., and Hidalgo, M. (2017). Adjuvant treatment for pancreatic ductal carcinoma. Clin. Transl. Oncol.","DOI":"10.1007\/s12094-017-1683-5"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.critrevonc.2017.04.011","article-title":"Toxicities of systemic agents in squamous cell carcinoma of the head and neck (SCCHN); A new perspective in the era of immunotherapy","volume":"115","author":"Saba","year":"2017","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/nature11540","article-title":"Serine is a natural ligand and allosteric activator of pyruvate kinase M2","volume":"491","author":"Chaneton","year":"2012","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"La Porta, C.A.M., Zapperi, S., and Sethna, J.P. (2012). Senescent Cells in Growing Tumors: Population Dynamics and Cancer Stem Cells. PLoS Comput. Biol., 8.","DOI":"10.1371\/journal.pcbi.1002316"},{"key":"ref_18","first-page":"374","article-title":"Potential Sources of Tumor Nitrogen","volume":"10","author":"Sherman","year":"1950","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Maddocks, O.D.K., Berkers, C.R., Mason, S.M., Zheng, L., Blyth, K., Gottlieb, E., and Vousden, K.H. (2013). Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature.","DOI":"10.1038\/nature11743"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1111\/febs.14081","article-title":"Essential amino acid mixtures drive cancer cells to apoptosis through proteasome inhibition and autophagy activation","volume":"284","author":"Bonfili","year":"2017","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.trecan.2015.07.003","article-title":"Cellular mechanisms underlying intertumoral heterogeneity","volume":"1","author":"Sutherland","year":"2015","journal-title":"Trends Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ebiom.2017.05.024","article-title":"The spasmogenic effects of the proteasome inhibitor carfilzomib on coronary resistance, vascular tone and reactivity","volume":"21","author":"Corsetti","year":"2017","journal-title":"EBioMedicine"},{"key":"ref_23","first-page":"354","article-title":"Protect and Counter-attack: Nutritional Supplementation with Essential Amino acid Ratios Reduces Doxorubicin\u2013induced Cardiotoxicity in vivo and promote Cancer Cell Death in vitro","volume":"6","author":"Corsetti","year":"2015","journal-title":"J. Cytol. Histol."},{"key":"ref_24","first-page":"1","article-title":"Autophagic disregulation in doxorubicin cardiomyopathy","volume":"104","author":"Bartlett","year":"2017","journal-title":"Life Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.amjcard.2008.03.009","article-title":"Effects of oral amino acid supplements on cardiac function and remodeling in patients with type 2 diabetes with mild to moderate left ventricular dysfunction","volume":"101","author":"Scognamiglio","year":"2008","journal-title":"Am. J. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E249","DOI":"10.1038\/nutd.2016.55","article-title":"Plasma-free amino acid profiles are predictors of cancer and diabetes development","volume":"7","author":"Bi","year":"2017","journal-title":"Nutr. Diabetes"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.celrep.2016.05.092","article-title":"Decreased consumption of branched chain amino acids improves metabolic health","volume":"16","author":"Fontana","year":"2016","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.cmet.2009.02.002","article-title":"A branched chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance","volume":"9","author":"Newgard","year":"2009","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.2337\/db07-0123","article-title":"Increasing dietary leucine intake reduces diet-induced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms","volume":"56","author":"Zhang","year":"2007","journal-title":"Diabetes"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.2169\/internalmedicine.51.7578","article-title":"Long-term branched-chain amino acid supplementation improves glucose tolerance in patients with nonalcoholic steatohepatitis-related cirrhosis","volume":"51","author":"Miyake","year":"2012","journal-title":"Intern. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1159\/000475604","article-title":"Increased incretin but not insulin response after oral versus intravenous branched chain amino aicds","volume":"70","author":"Gojda","year":"2017","journal-title":"Ann. Nutr. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, R., Li, H., Fan, W., Jin, Q., Chao, T., Wu, Y., Huang, J., Hao, L., and Yang, X. (2017). Leucine supplementation differently modulates branched-chain amino acid catabolism, mitochondrial function and metabolic profiles at the different stage of insulin resistance in rats on high-fat diet. Nutrients, 9.","DOI":"10.3390\/nu9060565"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"357","DOI":"10.18632\/aging.100040","article-title":"Growth and aging: A common molecular mechanism","volume":"1","author":"Blagosklonny","year":"2009","journal-title":"Aging"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.cmet.2010.08.016","article-title":"Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice","volume":"12","author":"Ragni","year":"2010","journal-title":"Cell Metab."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Edwards, C., Canfield, J., Copes, N., Brito, A., Rehan, M., Lipps, D., Brunquell, J., Westerheide, S.D., and Bradshaw, P.C. (2015). Mechanisms of amino acid-mediated lifespan extension in caenorrhabditis elegans. BMC Genet., 16.","DOI":"10.1186\/s12863-015-0167-2"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1097\/MCO.0000000000000235","article-title":"Branched-chain amino acids as biomarkers in diabetes","volume":"19","author":"Giezberg","year":"2016","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/0168-8278(90)90278-Y","article-title":"Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind, casein-controlled study","volume":"11","author":"Marchesini","year":"1990","journal-title":"J. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1200\/JCO.2009.24.9730","article-title":"Association of Skeletal Muscle Wasting with Treatment with Sorafenib in Patients with Advanced Renal Cell Carcinoma: Results From a Placebo-Controlled Study","volume":"28","author":"Antoun","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_39","unstructured":"National Cancer Institute (2006). Cancer Therapy Evaluation Program: Common Terminology Criteria for Adverse Events v3.0 (CTCAE)."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1146\/annurev.nutr.25.050304.092545","article-title":"Role of Dietary Proteins and Amino Acids in the Pathogenesis of Insulin Resistance","volume":"27","author":"Tremblay","year":"2007","journal-title":"Annu. Rev. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6A","DOI":"10.1016\/j.amjcard.2003.11.002","article-title":"Wasting and the substrate-to-energy controlled pathway: A role for insulin resistance and amino acids","volume":"93","author":"Dioguardi","year":"2004","journal-title":"Am. J. Cardiol."},{"key":"ref_42","first-page":"136","article-title":"Body Weight Loss and Tissue Wasting in Late Middle-Aged Mice on Slightly Imbalanced","volume":"17","author":"Corsetti","year":"2018","journal-title":"Essent.\/Non-essent. Amino Acids Diet. Front. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2174\/1871520615666150824152900","article-title":"Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?","volume":"16","author":"Flati","year":"2016","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pinheiro, D., Hannezo, E., Hersztberg, S., Bosveld, F., Gaugue, I., Balakireva, M., Wang, Z., Cristo, I., Rigaud, S.U., and Markova, O. (2017). Transmission of cytokines forces via E-cadherin dilution and actomyosin flows. Nature.","DOI":"10.1038\/nature22041"},{"key":"ref_45","first-page":"80","article-title":"Threonine metabolism and embryonic stem cell self-renewal","volume":"17","author":"Chen","year":"2014","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/nyas.12956","article-title":"One-carbon metabolism and epigenetics: Understanding the specificity","volume":"1363","author":"Mentch","year":"2016","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.1158\/0008-5472.CAN-12-0569","article-title":"Tryptophan Catabolism in Cancer: Beyond IDO and Tryptophan Depletion","volume":"72","author":"Platten","year":"2012","journal-title":"Cancer Res."},{"key":"ref_48","first-page":"204","article-title":"Overweight and obesity increase the risk for liver cancer in patients with liver cirrhosis and long-term oral supplementation with branched chain amino acid granules inhibits liver carcinogenesis in heavier patients with liver cirrhosis","volume":"35","author":"Muto","year":"2006","journal-title":"Hepatol. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1002\/jcp.22941","article-title":"Branched-Chain Amino Acids Prevent Insulin-Induced Hepatic Tumor Cell Proliferation by Inducing Apoptosis through mTORC1 and mTORC2-Dependent Mechanisms","volume":"227","author":"Hagiwara","year":"2012","journal-title":"J. Cell Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"397","DOI":"10.15252\/embj.201696010","article-title":"Nutrient sensing and TOR signaling in yeast and mammals","volume":"36","author":"Hall","year":"2017","journal-title":"EMBO J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.celrep.2016.12.077","article-title":"Arginine deprivation inhibits the Warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ASS-1deficient cancers","volume":"18","author":"Kremer","year":"2017","journal-title":"Cell Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"104","DOI":"10.4161\/auto.22399","article-title":"BCL2L11\/BIM. A novel molecular link between autophagy and apoptosis","volume":"9","author":"Luo","year":"2013","journal-title":"Autophagy"},{"key":"ref_53","first-page":"25","article-title":"Comprehensive effects of supplemented essential amino acids in patients with severe COPD and sarcopenia","volume":"73","author":"Aquilani","year":"2010","journal-title":"Monaldi Arch. Chest Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.clnu.2011.04.005","article-title":"Effect of essential amino acid supplementation on quality of life, amino acid profile and strength in institutionalized elderly patients","volume":"30","author":"Rondanelli","year":"2011","journal-title":"Clin. Nutr."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"26E","DOI":"10.1016\/j.amjcard.2008.02.078","article-title":"Morphometric changes induced by amino acid supplementation in skeletal and cardiac muscles of old mice","volume":"101","author":"Corsetti","year":"2008","journal-title":"Am. J. Cardiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.metabol.2005.08.023","article-title":"The effects of amino acids supplementation on hormonal responses to resistance training overreaching","volume":"55","author":"Kraemer","year":"2006","journal-title":"Metabolism"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3233\/s12349-010-0016-9","article-title":"Open phase II study on efficacy and safety of an oral amino acid functional cluster supplementation in cancer cachexia","volume":"3","author":"Madeddu","year":"2010","journal-title":"Mediterr. J. Nutr. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"35A","DOI":"10.1016\/j.amjcard.2003.11.008","article-title":"Nutritional supplementation with mixed essential aminoacids enhance myocyte survival, preserving mitochondrial functional capacity during ischemia-reperfusion injury","volume":"93","author":"Scarabelli","year":"2004","journal-title":"Am. J. Cardiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/cdd.2016.160","article-title":"One carbon, many roads","volume":"24","author":"Gottlieb","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1002\/hep.22074","article-title":"Inhibition of Adiponectin Production by Homocysteine: A Potential Mechanism for Alcoholic Liver Disease","volume":"47","author":"Song","year":"2008","journal-title":"Hepatology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"182","DOI":"10.3945\/ajcn.114.098418","article-title":"Prospective association between alcohol intake and hormone dependent cancer risk: Modulation by dietary fiber intake","volume":"102","author":"Chim","year":"2015","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"S65","DOI":"10.1016\/j.amepre.2013.10.025","article-title":"Folic Acid Fortification and Colorectal Cancer Risk","volume":"46","author":"Keum","year":"2014","journal-title":"Am. J. Prev. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1097\/MCO.0b013e32831cec62","article-title":"Too much folate\u2014A risk factor for cancer and cardiovascular disease?","volume":"12","author":"Sauer","year":"2009","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1056\/NEJM194806032382301","article-title":"Temporary remission in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl glutamic acid","volume":"238","author":"Farber","year":"1948","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1093\/jnci\/djp440","article-title":"Cardiotoxicity of Anticancer Drugs: The Need for Cardio-Oncology and Cardio-Oncological Prevention","volume":"102","author":"Albini","year":"2010","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"23955","DOI":"10.18632\/oncotarget.15053","article-title":"One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy","volume":"8","author":"Shuvalov","year":"2017","journal-title":"Oncotarget"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1038\/bjc.2017.118","article-title":"One-carbon metabolism in cancer","volume":"116","author":"Newman","year":"2017","journal-title":"Brit. J. Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.3945\/ajcn.2009.28064","article-title":"Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele","volume":"90","author":"Ericson","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6","DOI":"10.35946\/arcr.v35.1.02","article-title":"Alcohol Metabolism and Epigenetics Changes","volume":"35","author":"Zakhari","year":"2013","journal-title":"Alcohol. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"7521","DOI":"10.1158\/0008-5472.CAN-14-2643-T","article-title":"serine deprivation enhances antineoplastic activity of biguanides","volume":"74","author":"Gravel","year":"2014","journal-title":"Cancer Res."},{"key":"ref_71","unstructured":"Stolzemberg, G. (1978). Can an inquiry into the foundation of mathematics tell us anything interesting about mind?. Psychology and Biology of Language and Thought: Essay in Honor of Erich Lenneberg, Academic Press."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Kawaguchi, T., Shiraishi, K., Ito, T., Suzuki, K., Koreeda, C., Ohtake, T., Iwasa, M., Tokumoto, Y., Endo, R., and Kawamura, N.H. (2014). Branched-Chain Amino Acids Prevent Hepatocarcinogenesis and Prolong Survival of Patients With Cirrhosis. Clin. Gastroenterol. Hepatol., 1012\u20131018.e1.","DOI":"10.1016\/j.cgh.2013.08.050"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"MTOR signaling in growth, metabolism and disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12943-017-0648-1","article-title":"ROS signaling under metabolic stress: Cross-talk between AMPK and AKT pathway","volume":"16","author":"Zhao","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3389\/fonc.2016.00257","article-title":"Time and circumstances: Cancer cell metabolism at various stages of disease progression","volume":"6","author":"Weber","year":"2016","journal-title":"Front. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1146\/annurev-bioeng-071516-044546","article-title":"Glutaminolysis: A hallmark of cancer metabolism","volume":"19","author":"Yang","year":"2017","journal-title":"Ann. Rev. Biomed. Eng."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1038\/bjc.2017.113","article-title":"Hopefully devoted to Q: Targeting glutamine addiction in cancer","volume":"116","author":"Still","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Bezkorovainy, A., and Rafaelson, M.E. (1996). Chapter 20. Protein and amino acid metabolism. Concise Biochemistry, Marcel Dekker Inc.","DOI":"10.1201\/9781482273526-71"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S0753-3322(02)00273-1","article-title":"The metabolic basis of arginine nutrition and pharmacotherapy","volume":"56","author":"Flynn","year":"2002","journal-title":"Biomed. Pharmacother."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1753-4887.2005.tb00123.x","article-title":"The role of glutamine in intensive care unit patients: Mechanisms of action and clinical outcome","volume":"63","author":"Coeffier","year":"2005","journal-title":"Nutr. Rev."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e123","DOI":"10.1016\/j.archger.2010.09.005","article-title":"Effects of oral amino acid supplementation on long-term-care-acquired infections in elderly patients","volume":"52","author":"Aquilani","year":"2011","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.neuint.2012.02.001","article-title":"Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: Role of glutamine redefined","volume":"60","author":"Desjardins","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1042\/cs0940313","article-title":"Distribution of glutaminase and glutamine synthase activities in the human gastrointestinal tract","volume":"94","author":"James","year":"1998","journal-title":"Clin. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1046\/j.1471-4159.2003.01981.x","article-title":"Glutamine efflux from astrocytes is mediated by multiple pathways","volume":"87","author":"Deitmer","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1177\/0148607112460682","article-title":"Side effects of long-term glutamine supplementation","volume":"37","author":"Holecek","year":"2013","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1093\/jn\/137.6.1357","article-title":"Glutamine Directly Downregulates Glutamine Synthetase Protein Levels in Mouse C2C12 Skeletal Muscle Myotubes","volume":"137","author":"Huang","year":"2007","journal-title":"J. Nutr."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1017\/S000711450769936X","article-title":"Amino acids and immune function","volume":"98","author":"Li","year":"2007","journal-title":"Brit. J. Nutr."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1007\/s00726-008-0063-4","article-title":"The metabolism of proline, a stress substrate, modulates carcinogenic pathways","volume":"35","author":"Phang","year":"2008","journal-title":"Amino Acids"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/biof.1036","article-title":"Proline dehydrogenase (oxidase) in cancer","volume":"38","author":"Liu","year":"2012","journal-title":"Biofactors"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/0003-9861(83)90010-3","article-title":"Transfer of reducing equivalents into mitochondria by the interconversion of proline and \u03941-pyrroline 5-carboxylate","volume":"225","author":"Hagedorn","year":"1983","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"60","DOI":"10.3389\/fonc.2012.00060","article-title":"The proline regulatory axis and cancer","volume":"2","author":"Phang","year":"2012","journal-title":"Front. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"18697","DOI":"10.1073\/pnas.1415669112","article-title":"A long noncoding RNA connects c-Myc to tumor metabolism","volume":"111","author":"Hung","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.15252\/embj.201796999","article-title":"C-MYC mRNA tail tale about glutamine control of transcription","volume":"36","author":"Dang","year":"2017","journal-title":"EMBO J."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1097\/00075197-200401000-00009","article-title":"Recent avances in arginine metabolism","volume":"7","author":"Morris","year":"2004","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.cell.2013.09.025","article-title":"Vander Heiden MG. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells","volume":"155","author":"Israelsen","year":"2013","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3631\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T04:35:34Z","timestamp":1775277334000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,17]]},"references-count":95,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["ijms19113631"],"URL":"https:\/\/doi.org\/10.3390\/ijms19113631","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints201810.0428.v1","asserted-by":"object"}]},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,17]]}}}