{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T01:07:03Z","timestamp":1778634423656,"version":"3.51.4"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Syst Biol"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>In the field of drug discovery, assessing the potential of multidrug therapies isa difficult task because of the combinatorial complexity (both theoretical andexperimental) and because of the requirements on the selectivity of the therapy.To cope with this problem, we have developed a novel method for the systematic insilico investigation of synergistic effects of currently available drugs ongenome-scale metabolic networks.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The algorithm finds the optimal combination of drugs which guarantees theinhibition of an objective function, while minimizing the side effect on the othercellular processes. Two different applications are considered: finding drugsynergisms for human metabolic diseases (like diabetes, obesity and hypertension)and finding antitumoral drug combinations with minimal side effect on the normalhuman cell. The results we obtain are consistent with some of the availabletherapeutic indications and predict new multiple drug treatments. A clusteranalysis on all possible interactions among the currently available drugsindicates a limited variety on the metabolic targets for the approved drugs.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The in silico prediction of drug synergisms can represent an important tool forthe repurposing of drugs in a realistic perspective which considers also theselectivity of the therapy. Moreover, for a more profitable exploitation ofdrug-drug interactions, we have shown that also experimental drugs which have adifferent mechanism of action can be reconsider as potential ingredients of newmulticompound therapeutic indications. Needless to say the clues provided by acomputational study like ours need in any case to be thoroughly evaluatedexperimentally.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-6-115","type":"journal-article","created":{"date-parts":[[2012,8,29]],"date-time":"2012-08-29T10:14:19Z","timestamp":1346235259000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Predicting and characterizing selective multiple drug treatments for metabolicdiseases and cancer"],"prefix":"10.1186","volume":"6","author":[{"given":"Giuseppe","family":"Facchetti","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattia","family":"Zampieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Altafini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2012,8,29]]},"reference":[{"key":"1147_CR1","doi-asserted-by":"publisher","first-page":"215.","DOI":"10.1038\/msb.2008.51","volume":"4","author":"J Lehar","year":"2008","unstructured":"Lehar J, Krueger A, Zimmermann G, Borisy A: High-order combination effect and biological robustness. Mol Syst Biol. 2008, 4: 215.-10.1038\/msb.2008.51.","journal-title":"Mol Syst Biol"},{"issue":"3","key":"1147_CR2","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1124\/pr.58.3.10","volume":"58","author":"T Chou","year":"2006","unstructured":"Chou T: Theoretical basis, experimental design, and computerized simulation of synergismand antagonism in drug combination studies. Pharmacol Rev. 2006, 58 (3): 621-681. 10.1124\/pr.58.3.10.","journal-title":"Pharmacol Rev"},{"key":"1147_CR3","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.tips.2005.02.007","volume":"26","author":"P Csermely","year":"2005","unstructured":"Csermely P, Agoston V, Pongor S: The efficiency of multi-target drugs: the network approach might help drugdesign. Trends Pharmacol Sci. 2005, 26: 178-182. 10.1016\/j.tips.2005.02.007.","journal-title":"Trends Pharmacol Sci"},{"issue":"4","key":"1147_CR4","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/ng1755","volume":"38","author":"P Yeh","year":"2006","unstructured":"Yeh P, Tschumi A, Kishony R: Functional classification of drugs by properties of their pairwise interaction. Nature Gen. 2006, 38 (4): 489-494. 10.1038\/ng1755.","journal-title":"Nature Gen"},{"key":"1147_CR5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrd1609","volume":"4","author":"C Keith","year":"2005","unstructured":"Keith C, Borisy A, Stockwell B: Multicomponent therapeutics for networked systems. Nat Rev Drug Discov. 2005, 4: 1-8.","journal-title":"Nat Rev Drug Discov"},{"key":"1147_CR6","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/msb4100133","volume":"3","author":"P Yeh","year":"2007","unstructured":"Yeh P, Kishony R: Networks from drug-drug surface. Mol Syst Biol. 2007, 3: 85-87.","journal-title":"Mol Syst Biol"},{"issue":"1","key":"1147_CR7","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/ng1489","volume":"37","author":"D Segr\u00e9","year":"2005","unstructured":"Segr\u00e9 D, De Luna A, Church G, Kishony R: Modular epistasis in yeast metabolism. Nat Genet. 2005, 37 (1): 77-83.","journal-title":"Nat Genet"},{"key":"1147_CR8","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/msb.2009.56","volume":"5","author":"P Suthers","year":"2005","unstructured":"Suthers P, Zomorrodi A, Maranas C: Genome-scale gene\/reaction essentiality and synthetic lethality analysis. Mol Syst Biol. 2005, 5: 301-","journal-title":"Mol Syst Biol"},{"issue":"6","key":"1147_CR9","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1002\/bit.10803","volume":"84","author":"A Burgard","year":"2003","unstructured":"Burgard A, Pharkya P, Maranas C: OptKnock: A bilevel programming framework for identifying gene knockout strategiesfor microbial strain optimization. Biotechnol Bioeng. 2003, 84 (6): 647-657. 10.1002\/bit.10803.","journal-title":"Biotechnol Bioeng"},{"key":"1147_CR10","first-page":"291","volume":"13","author":"P Sridhar","year":"2008","unstructured":"Sridhar P, Song B, Kahveci T, Ranka S: Mining metabolic networks for optimal drug targets. Pac Symp Biocomput. 2008, 13: 291-302.","journal-title":"Pac Symp Biocomput"},{"key":"1147_CR11","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1038\/nrc1691","volume":"5","author":"W Kaelin","year":"2005","unstructured":"Kaelin W: The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005, 5: 689-698. 10.1038\/nrc1691.","journal-title":"Nat Rev Cancer"},{"issue":"21","key":"1147_CR12","doi-asserted-by":"publisher","first-page":"8685","DOI":"10.1073\/pnas.0701361104","volume":"104","author":"K Goh","year":"2007","unstructured":"Goh K, Cusick M, Valle D, Childs B, Vidal M, Barab\u00e1si A: The human disease network. Proc Natl Acad Sci USA. 2007, 104 (21): 8685-8690. 10.1073\/pnas.0701361104.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"3","key":"1147_CR13","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/0026-0495(95)90313-5","volume":"44","author":"E Ferrannini","year":"1995","unstructured":"Ferrannini E: Physiological and metabolic consequences of obesity. Metabolism. 1995, 44 (3): 15-17.","journal-title":"Metabolism"},{"key":"1147_CR14","doi-asserted-by":"publisher","first-page":"501.","DOI":"10.1038\/msb.2011.35","volume":"7","author":"O Folger","year":"2011","unstructured":"Folger O, Jerby L, Frezza C, Gottlieb E, Ruppin E, Shlomi T: Predicting selective drug targets in cancer through metabolic networks. Mol Syst Biol. 2011, 7: 501.-10.1038\/msb.2011.35.","journal-title":"Mol Syst Biol"},{"key":"1147_CR15","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9780511790515","volume-title":"Systems Biology: Properties of Reconstructed Networks","author":"B Palsson","year":"2006","unstructured":"Palsson B: Systems Biology: Properties of Reconstructed Networks. 2006, New York: Cambridge University Press"},{"issue":"4","key":"1147_CR16","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1093\/bib\/bbp011","volume":"10","author":"K Raman","year":"2009","unstructured":"Raman K, Chandra N: Flux balance analysis of biological systems: applications and challenges. Brief Bioinform. 2009, 10 (4): 435-449. 10.1093\/bib\/bbp011.","journal-title":"Brief Bioinform"},{"issue":"9","key":"1147_CR17","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1038\/ng1856","volume":"38","author":"D Deutscher","year":"2006","unstructured":"Deutscher D, Meilijson I, Kupiec M, Ruppin E: Multiple knockout analysis of genetic robustness in the yeast metabolicnetwork. Nat Gen. 2006, 38 (9): 993-998. 10.1038\/ng1856.","journal-title":"Nat Gen"},{"key":"1147_CR18","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/1752-0509-3-81","volume":"3","author":"A Vazquez","year":"2009","unstructured":"Vazquez A: Optimal drug combinations and minimal hitting sets. BMC Syst Biol. 2009, 3: 81-87. 10.1186\/1752-0509-3-81.","journal-title":"BMC Syst Biol"},{"issue":"2","key":"1147_CR19","doi-asserted-by":"publisher","first-page":"026104","DOI":"10.1063\/1.3456056","volume":"20","author":"M Imielinski","year":"2010","unstructured":"Imielinski M, Belta B: Deep epistasis in human metabolism. Chaos. 2010, 20 (2): 026104-10.1063\/1.3456056.","journal-title":"Chaos"},{"issue":"23","key":"1147_CR20","doi-asserted-by":"publisher","first-page":"15112","DOI":"10.1073\/pnas.232349399","volume":"99","author":"D Segr\u00e9","year":"2002","unstructured":"Segr\u00e9 D, Vitkup D, Church G: Analysis of optimality in natural and perturbed metabolic networks. Proc Natl Acad Sci USA. 2002, 99 (23): 15112-15117. 10.1073\/pnas.232349399.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"21","key":"1147_CR21","doi-asserted-by":"publisher","first-page":"7695","DOI":"10.1073\/pnas.0406346102","volume":"102","author":"T Shlomi","year":"2005","unstructured":"Shlomi T, Berkman O, Ruppin E: Regulatory on\/off minimization of metabolic flux changes after geneticperturbations. Proc Natl Acad Sci USA. 2005, 102 (21): 7695-7700. 10.1073\/pnas.0406346102.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"2","key":"1147_CR22","doi-asserted-by":"publisher","first-page":"e1001294","DOI":"10.1371\/journal.pgen.1001294","volume":"7","author":"E Snitkin","year":"2011","unstructured":"Snitkin E, Mackay T, Segr\u00e8 D: Epistatic interaction maps relative to multiple metabolic phenotypes. PLoS Genet. 2011, 7 (2): e1001294-10.1371\/journal.pgen.1001294.","journal-title":"PLoS Genet"},{"issue":"2","key":"1147_CR23","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1093\/clinids\/4.2.196","volume":"4","author":"A Salter","year":"1982","unstructured":"Salter A: Overview. Trimethoprim-sulfamethoxazole: an assessment of more than 12 years ofuse. Rev Infect Dis. 1982, 4 (2): 196-236. 10.1093\/clinids\/4.2.196.","journal-title":"Rev Infect Dis"},{"issue":"3","key":"1147_CR24","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.pneurobio.2010.06.008","volume":"92","author":"O Weinreb","year":"2010","unstructured":"Weinreb O, Amit T, Bar-Am O, Youdim M: Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor withneuroprotective activity. Prog Neurobiol. 2010, 92 (3): 330-344. 10.1016\/j.pneurobio.2010.06.008.","journal-title":"Prog Neurobiol"},{"issue":"6","key":"1147_CR25","doi-asserted-by":"publisher","first-page":"1777","DOI":"10.1073\/pnas.0610772104","volume":"104","author":"N Duarte","year":"2007","unstructured":"Duarte N, Becker S, Jamshidi N, Thiele I, et al.: Global reconstruction of the human metabolic network based on genomic andbibliomic data. PNAS. 2007, 104 (6): 1777-1782. 10.1073\/pnas.0610772104.","journal-title":"PNAS"},{"issue":"Suppl 1","key":"1147_CR26","doi-asserted-by":"publisher","first-page":"D1035","DOI":"10.1093\/nar\/gkq1126","volume":"39","author":"C Knox","year":"2011","unstructured":"Knox C, Law V, Jewison T, Liu P, Ly S, Frolkis A, Pon A, Banco K, Mak C, et al.: DrugBank 3.0: a comprehensive resource for \u2018omics\u2019 research ondrugs. Nucleic Acids Res. 2011, 39 (Suppl 1): D1035-D1041.","journal-title":"Nucleic Acids Res"},{"issue":"2","key":"1147_CR27","first-page":"537","volume":"38","author":"M Mansour","year":"2010","unstructured":"Mansour M, Schwarts D, Judd R, Akingbemi B, Braden T, Morrison E, Dennis J, Bartol F, Hazi A, Napier I, Abdel-Mageed A: Thiazolidinediones\/PPAR\u03b3 agonists and fatty acid synthase inhibitors as anexperimental combination therapy for prostate cancer. Int J Oncol. 2010, 38 (2): 537-546.. 103892\/ijo2010877. 103892\/ijo2010877 103892\/ijo2010877","journal-title":"Int J Oncol"},{"issue":"2","key":"1147_CR28","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/S0962-8924(99)01694-3","volume":"10","author":"C Luberto","year":"2000","unstructured":"Luberto C, Hannun Y: Ceramide in the eukaryotic stress response. Trends Cell Biol. 2000, 10 (2): 73-80. 10.1016\/S0962-8924(99)01694-3.","journal-title":"Trends Cell Biol"},{"key":"1147_CR29","doi-asserted-by":"publisher","first-page":"25847","DOI":"10.1074\/jbc.R200008200","volume":"277","author":"L Obeid","year":"2002","unstructured":"Obeid L, Hannun Y: The Ceramide-centric universe of lipid-mediated cell regulation: stress encountersof the lipid kind. J Biol Chem. 2002, 277: 25847-25850. 10.1074\/jbc.R200008200.","journal-title":"J Biol Chem"},{"key":"1147_CR30","doi-asserted-by":"publisher","first-page":"E211\u2014E224","DOI":"10.1152\/ajpendo.91014.2008","volume":"297","author":"G Yang","year":"2009","unstructured":"Yang G, Badeanlou L, Bielawski J, Roberts A, Hannun Y, Samad F: Central role of ceramide biosynthesis in body weight regulation, energymetabolism, and the metabolic syndrome. Am J Physiol Endocrinol Metab. 2009, 297: E211\u2014E224-[http:\/\/ajpendo.physiology.org\/content\/297\/1\/E211.abstract],","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"6","key":"1147_CR31","doi-asserted-by":"publisher","first-page":"1671","DOI":"10.1124\/mol.104.003681","volume":"66","author":"G Triola","year":"2004","unstructured":"Triola G, Fabrias G, Dragusin M, Niederhausen L, Broere R, et al.: Specificity of the Dihydroceramide Desaturase InhibitorN-[(1R,2S)-2-Hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11) in Primary Cultured Cerebellar Neurons. Mol Pharmacol. 2004, 66 (6): 1671-1678. 10.1124\/mol.104.003681.","journal-title":"Mol Pharmacol"},{"key":"1147_CR32","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1002\/cmdc.200700325","volume":"3","author":"J Munoz-Olaya","year":"2009","unstructured":"Munoz-Olaya J, Matabosch X, Bedia C, Egido-Gabs M, Casas J, et al.: Synthesis and biological activity of a novel inhibitor of DihydroceramideDesaturase. Chem Med Chem. 2009, 3: 946-953.","journal-title":"Chem Med Chem"},{"key":"1147_CR33","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.bcp.2004.03.009","volume":"68","author":"G Llaverias","year":"2004","unstructured":"Llaverias G, Lacasa D, Vi\u00f1als M, V\u00e1zquez-Carrera M, S\u00e1nchez R, Laguna J, Alegret M: Reduction of intracellular cholesterol accumulation in THP-1 macrophages by acombination of rosiglitazone and atorvastatin. Biochem pharmacol. 2004, 68: 155-163. 10.1016\/j.bcp.2004.03.009.","journal-title":"Biochem pharmacol"},{"issue":"9","key":"1147_CR34","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/S0002-9149(02)02659-0","volume":"90","author":"M Freed","year":"2002","unstructured":"Freed M, Ratner R, Marcovina S, Kreider M, Biswas N, Cohen B, Brunzell J: Effects of Rosiglitazone alone and in combination with Atorvastatin on themetabolic abnormalities in type 2 diabetes mellitus. Ame J Cardiology. 2002, 90 (9): 947-952. 10.1016\/S0002-9149(02)02659-0.","journal-title":"Ame J Cardiology"},{"key":"1147_CR35","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/1745-6215-8-21","volume":"8","author":"G De Berardis","year":"2007","unstructured":"De Berardis G, Sacco M, Evangelista V, Filippi A, Giorda C, Tognoni G, Valentini U, Nicolucci A, et al.: Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial inDiabetes (ACCEPT-D): design of a randomized study of the efficacy of low-doseaspirin in the prevention of cardiovascular events in subjects with diabetesmellitus treated with statins. Trials. 2007, 8: 21-10.1186\/1745-6215-8-21.","journal-title":"Trials"},{"issue":"6","key":"1147_CR36","doi-asserted-by":"crossref","first-page":"e9011","DOI":"10.1161\/circ.106.6.e9011","volume":"106","author":"P Armstrong","year":"2002","unstructured":"Armstrong P, Lorell B, Nissen S, Borer J: 97th Meeting of the Cardiovascular and Renal Drugs Advisory Committee July 18thand 19th, 2002. Circulation. 2002, 106 (6): e9011-e9012.","journal-title":"Circulation"},{"issue":"9","key":"1147_CR37","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1002\/pros.20951","volume":"69","author":"T Murtola","year":"2009","unstructured":"Murtola T, Pennanen P, Syv\u00e4l\u00e4 H, Bl\u00e4uer M, Ylikomi T, Tammela T: Effects of simvastatin, acetylsalicylic acid, and rosiglitazone on proliferationof normal and cancerous prostate epithelial cells at therapeuticconcentrations. Prostate. 2009, 69 (9): 1017-1023. 10.1002\/pros.20951.","journal-title":"Prostate"},{"issue":"5","key":"1147_CR38","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1200\/JCO.1983.1.5.337","volume":"1","author":"G Weiss","year":"1983","unstructured":"Weiss G, Garnick M, Osteen R, Steele G, Wilson R, Schade D, Kaplan W, Boxt L, Kandarpa K, Mayer R: Long-term hepatic arterial infusion of 5-fluorodeoxyuridine for liver metastasesusing an implantable infusion pump. J Clin Oncology. 1983, 1 (5): 337-344.","journal-title":"J Clin Oncology"},{"key":"1147_CR39","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1038\/223848a0","volume":"223","author":"S Carter","year":"1969","unstructured":"Carter S, Franklin T, Jones D, Leonard B, Mills S, Turner R, Turner W: Mycophenolic acid: an anti-cancer compound with unusual properties. Nature. 1969, 223: 848-850. 10.1038\/223848a0.","journal-title":"Nature"},{"issue":"16","key":"1147_CR40","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1056\/NEJM197504172921607","volume":"292","author":"H Bleich","year":"1975","unstructured":"Bleich H, Boro E, Frei III E, Jaffe N, Tattersall M, Pitman S, Parker L: New approaches to cancer chemotherapy with methotrexate. New England J Med. 1975, 292 (16): 846-851. 10.1056\/NEJM197504172921607.","journal-title":"New England J Med"},{"issue":"5","key":"1147_CR41","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1634\/theoncologist.9-5-482","volume":"9","author":"M Hazarika","year":"2004","unstructured":"Hazarika M, White R, Johnson J, Pazdur R: FDA drug approval summaries: Pemetrexed (Alimta\u00ae). The oncologist. 2004, 9 (5): 482-488. 10.1634\/theoncologist.9-5-482.","journal-title":"The oncologist"},{"issue":"10","key":"1147_CR42","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.3109\/10428194.2010.496506","volume":"51","author":"K Borden","year":"2010","unstructured":"Borden K, Culjkovic-Kraljacic B: Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond?. Leukemia Lymphoma. 2010, 51 (10): 1805-10.3109\/10428194.2010.496506.","journal-title":"Leukemia Lymphoma"},{"issue":"8","key":"1147_CR43","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1158\/1055-9965.EPI-06-0128","volume":"15","author":"S Lam","year":"2006","unstructured":"Lam S, McWilliams A, MacAulay C, Wattenberg L, Szabo E, et al.: A phase I study of myo-inositol for lung cancer chemoprevention. Cancer Epidemiol Biomarkers Prev. 2006, 15 (8): 1526-1531. 10.1158\/1055-9965.EPI-06-0128.","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"4","key":"1147_CR44","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1002\/ijc.23593","volume":"123","author":"S Cho","year":"2008","unstructured":"Cho S, Kim J, Kim J, Lee J, Jung H, Song I: Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts,and attenuates colitis-associated colon cancer in mice. Int J Cancer. 2008, 123 (4): 951-957. 10.1002\/ijc.23593.","journal-title":"Int J Cancer"},{"issue":"2","key":"1147_CR45","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1158\/1535-7163.MCT-08-0664","volume":"8","author":"P Baumann","year":"2009","unstructured":"Baumann P, Mandl-Weber S, V\u00f6lkl A, Adam C, Bumeder I, Oduncu F, Schmidmaier R: Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis anddiminishes proliferation of multiple myeloma cells. Mol cancer ther. 2009, 8 (2): 366-10.1158\/1535-7163.MCT-08-0664.","journal-title":"Mol cancer ther"},{"issue":"5","key":"1147_CR46","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/S0145-2126(99)00198-8","volume":"24","author":"G Zhang","year":"2000","unstructured":"Zhang G, Tu C, Zhang G, Zhou G, Zheng W: Indomethacin induces apoptosis and inhibits proliferation in chronic myeloidleukemia cells. Leukemia res. 2000, 24 (5): 385-392. 10.1016\/S0145-2126(99)00198-8.","journal-title":"Leukemia res"},{"issue":"5","key":"1147_CR47","doi-asserted-by":"publisher","first-page":"845","DOI":"10.3171\/jns.1997.86.5.0845","volume":"86","author":"U Schrell","year":"1997","unstructured":"Schrell U, Rittig M, Anders M, Kiesewetter F, Marschalek R, Koch U, Fahlbusch R: Hydroxyurea for treatment of unresectable and recurrent meningiomas. I. Inhibitionof primary human meningioma cells in culture and in meningioma transplants byinduction of the apoptotic pathway. J Neurosurg. 1997, 86 (5): 845-852. 10.3171\/jns.1997.86.5.0845.","journal-title":"J Neurosurg"},{"issue":"Suppl 2","key":"1147_CR48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1634\/theoncologist.6-suppl_2-1","volume":"6","author":"K Antman","year":"2001","unstructured":"Antman K: Introduction: the history of arsenic trioxide in cancer therapy. The oncologist. 2001, 6 (Suppl 2): 1-2.","journal-title":"The oncologist"},{"issue":"17","key":"1147_CR49","doi-asserted-by":"crossref","first-page":"3068","DOI":"10.1200\/JCO.2000.18.17.3068","volume":"18","author":"H von der Maase","year":"2000","unstructured":"von der Maase H, Hansen S, Roberts J, Dogliotti L, Oliver T, Moore M, Bodrogi I, Albers P, Knuth A, Lippert C, et al.: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, andcisplatin in advanced or metastatic bladder cancer: results of a large,randomized, multinational, multicenter, phase III study. J Clin Oncology. 2000, 18 (17): 3068-3077.","journal-title":"J Clin Oncology"},{"issue":"2","key":"1147_CR50","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1021\/jm00344a014","volume":"25","author":"C Temple Jr","year":"1982","unstructured":"Temple Jr C, Bennett Jr L, Rose J, Elliott R, Montgomery J: Synthesis of pseudocofactor analogs as potential inhibitors of the folateenzymes. J Med Chem. 1982, 25 (2): 161-166. 10.1021\/jm00344a014.","journal-title":"J Med Chem"},{"key":"1147_CR51","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/0005-2760(81)90194-6","volume":"663","author":"M Mahfouz","year":"1981","unstructured":"Mahfouz M, Johnson S, Holman R: Inhibition of desaturation of palmitic, linoleic and eicosa-8, 11, 14-trienoicacids in vitro by isomeric cis-octadecenoic acids. Biochimica et Biophysica Acta (BBA)-Lipids and Lipid Metabolism. 1981, 663: 58-68. 10.1016\/0005-2760(81)90194-6.","journal-title":"Biochimica et Biophysica Acta (BBA)-Lipids and Lipid Metabolism"},{"key":"1147_CR52","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1006\/taap.1993.1003","volume":"118","author":"T Borges","year":"1993","unstructured":"Borges T, Glauert H, Robertson L: Perfluorodecanoic acid noncompetitively inhibits the peroxisomal enzymes enoyl-CoAhydratase and 3-hydroxyacyl-CoA dehydrogenase. Toxicol Appl Pharmacol. 1993, 118: 8-15. 10.1006\/taap.1993.1003.","journal-title":"Toxicol Appl Pharmacol"},{"issue":"44","key":"1147_CR53","doi-asserted-by":"publisher","first-page":"10755","DOI":"10.1021\/bi00108a021","volume":"30","author":"K Tserng","year":"1991","unstructured":"Tserng K, Jin S, Hoppel C: Spiropentaneacetic acid as a specific inhibitor of medium-chain acyl-CoAdehydrogenase. Biochemistry. 1991, 30 (44): 10755-10760. 10.1021\/bi00108a021.","journal-title":"Biochemistry"},{"issue":"1","key":"1147_CR54","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1128\/JB.01123-08","volume":"191","author":"V Mazumdar","year":"2009","unstructured":"Mazumdar V, Snitkin E, Amar S, Segr\u00e9 D: Metabolic network model of a human oral pathogen. J Bacteriol. 2009, 191 (1): 74-90. 10.1128\/JB.01123-08.","journal-title":"J Bacteriol"},{"key":"1147_CR55","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1126\/science.1058709","volume":"292","author":"L Hooper","year":"2001","unstructured":"Hooper L, Gordon J: Commensal host\u2013bacterial relationships in the gut. Science. 2001, 292: 1115-1118. 10.1126\/science.1058709.","journal-title":"Science"},{"key":"1147_CR56","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1006\/jtbi.1993.1203","volume":"165","author":"B Palsson","year":"1993","unstructured":"Palsson B, Varma A: Metabolic capabilities of Escherichia coli II: optimal growth pattern. J Theor Biol. 1993, 165: 503-522. 10.1006\/jtbi.1993.1203.","journal-title":"J Theor Biol"},{"key":"1147_CR57","volume-title":"Foundations of bilevel programming","author":"S Dempe","year":"2010","unstructured":"Dempe S: Foundations of bilevel programming. 2010, New York: Kluwer Academic Publisher"},{"key":"1147_CR58","volume-title":"Understanding and Using Linear Programming","author":"Matou\u0161ek J G\u00e4rtner B","year":"2000","unstructured":"Matou\u0161ek J G\u00e4rtner B: Understanding and Using Linear Programming. 2000, Berlin: Springer"},{"key":"1147_CR59","volume-title":"Theory of Linear and Integer Programming","author":"A Schrijver","year":"1986","unstructured":"Schrijver A: Theory of Linear and Integer Programming. 1986, New York: John Wiley Sons"}],"container-title":["BMC Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1752-0509-6-115.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T01:43:51Z","timestamp":1630547031000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcsystbiol.biomedcentral.com\/articles\/10.1186\/1752-0509-6-115"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,8,29]]},"references-count":59,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["1147"],"URL":"https:\/\/doi.org\/10.1186\/1752-0509-6-115","relation":{},"ISSN":["1752-0509"],"issn-type":[{"value":"1752-0509","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,8,29]]},"assertion":[{"value":"18 May 2012","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2012","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2012","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"115"}}