{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T01:35:31Z","timestamp":1778204131921,"version":"3.51.4"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2019,12,10]],"date-time":"2019-12-10T00:00:00Z","timestamp":1575936000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2019,12,10]],"date-time":"2019-12-10T00:00:00Z","timestamp":1575936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Invest New Drugs"],"published-print":{"date-parts":[[2020,10]]},"DOI":"10.1007\/s10637-019-00883-4","type":"journal-article","created":{"date-parts":[[2019,12,16]],"date-time":"2019-12-16T15:35:56Z","timestamp":1576510556000},"page":"1236-1246","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["[HuArgI (co)-PEG5000]-induced arginine deprivation leads to autophagy dependent cell death in pancreatic cancer cells"],"prefix":"10.1007","volume":"38","author":[{"given":"Nathalie","family":"Khalil","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9587-7758","authenticated-orcid":false,"given":"Ralph J.","family":"Abi-Habib","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,12,10]]},"reference":[{"issue":"3","key":"883_CR1","doi-asserted-by":"publisher","first-page":"273","DOI":"10.7150\/ijbs.14951","volume":"12","author":"S Chand","year":"2016","unstructured":"Chand S, O'Hayer K, Blanco FF, Winter JM, Brody JR (2016) The landscape of pancreatic Cancer therapeutic resistance mechanisms. Int J Biol Sci 12(3):273\u2013282","journal-title":"Int J Biol Sci"},{"key":"883_CR2","doi-asserted-by":"crossref","unstructured":"Liu Q, Stewart J, Wang H, Rashid A, Zhao J, Katz MH, Lee JE, Fleming JB, Maitra A, Wolff RA, Varadhachary GR, Krishnan S, Wang H (2017) Reduced expression of argininosuccinate synthetase 1 has a negative prognostic impact in patients with pancreatic ductal adenocarcinoma. PLoS One 12(2)","DOI":"10.1371\/journal.pone.0171985"},{"issue":"5","key":"883_CR3","doi-asserted-by":"publisher","first-page":"277","DOI":"10.3322\/caac.20073","volume":"60","author":"A Jemal","year":"2010","unstructured":"Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60(5):277\u2013300","journal-title":"CA Cancer J Clin"},{"issue":"4","key":"883_CR4","doi-asserted-by":"publisher","first-page":"212","DOI":"10.3322\/caac.20121","volume":"61","author":"R Siegel","year":"2011","unstructured":"Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212\u2013236","journal-title":"CA Cancer J Clin"},{"issue":"2","key":"883_CR5","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/S030-43835(02)00693-6","volume":"191","author":"LJ Shen","year":"2003","unstructured":"Shen LJ, Lin WC, Beloussow K, Shen WC (2003) Resistance to the anti-proliferative activity of recombinant arginine deiminase in cell culture correlates with the endogenous enzyme, argininosuccinate synthetase. Cancer Lett 191(2):165\u2013170","journal-title":"Cancer Lett"},{"issue":"1","key":"883_CR6","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.canlet.2005.01.007","volume":"231","author":"LJ Shen","year":"2006","unstructured":"Shen LJ, Beloussow K, Shen WC (2006) Modulation of arginine metabolic pathways as the potential anti-tumor mechanism of recombinant arginine deiminase. Cancer Lett 231(1):30\u201335","journal-title":"Cancer Lett"},{"issue":"6","key":"883_CR7","first-page":"1495","volume":"25","author":"A Manca","year":"2011","unstructured":"Manca A, Sini MC, Izzo F, Ascierto PA, Tatangelo F, Botti G, Gentilcore G, Capone M, Mozzillo N, Rozzo C, Cossu A, Tanda F, Palmieri G (2011) Induction of arginosuccinate synthetase (ASS) expression affects the antiproliferative activity of arginine deiminase (ADI) in melanoma cells. Oncol Rep 25(6):1495\u20131502","journal-title":"Oncol Rep"},{"issue":"1","key":"883_CR8","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1158\/0008-5472.CAN-06-1945","volume":"67","author":"PN-M Cheng","year":"2007","unstructured":"Cheng PN-M, Lam T-L, Lam W-M, Tsui S-M, Cheng AW-M, Lo W-H et al (2007) Pegylated recombinant human Arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion. Cancer Res 67(1):309\u2013317","journal-title":"Cancer Res"},{"issue":"4","key":"883_CR9","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1002\/ijc.22322","volume":"120","author":"CY Yoon","year":"2007","unstructured":"Yoon CY, Shim YJ, Kim EH, Lee JH, Won NH, Kim JH, Park IS, Yoon DK, Min BH (2007) Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase. Int J Cancer 120(4):897\u2013905","journal-title":"Int J Cancer"},{"issue":"25","key":"883_CR10","doi-asserted-by":"publisher","first-page":"5214","DOI":"10.1182\/blood-2009-12-258822","volume":"115","author":"CP Hernandez","year":"2010","unstructured":"Hernandez CP, Morrow K, Lopez-Barcons LA, Zabaleta J, Sierra R, Velasco C, Cole J, Rodriguez PC (2010) Pegylated arginase I: a potential therapeutic approach in T-ALL. Blood. 115(25):5214\u20135221","journal-title":"Blood."},{"issue":"3","key":"883_CR11","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1593\/tlo.10265","volume":"4","author":"ES Glazer","year":"2011","unstructured":"Glazer ES, Stone EM, Zhu C, Massey KL, Hamir AN, Curley SA (2011) Bioengineered human arginase I with enhanced activity and stability controls hepatocellular and pancreatic carcinoma xenografts. Transl Oncol 4(3):138\u2013146 Epub 2011 Jun 1","journal-title":"Transl Oncol"},{"issue":"11","key":"883_CR12","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1016\/j.leukres.2013.08.007","volume":"37","author":"R Tanios","year":"2013","unstructured":"Tanios R, Bekdash A, Kassab E, Stone E, Georgiou G, Frankel AE, Abi-Habib RJ (2013) Human recombinant arginase I(co)-PEG5000 [HuArgI(co)-PEG5000]-induced arginine depletion is selectively cytotoxic to human acute myeloid leukemia cells. Leuk Res 37(11):1565\u20131571","journal-title":"Leuk Res"},{"issue":"1","key":"883_CR13","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s11060-014-1698-5","volume":"122","author":"O Khoury","year":"2015","unstructured":"Khoury O, Ghazale N, Stone E, El-Sibai M, Frankel AE, Abi-Habib RJ (2015) Human recombinant arginase I (co)-PEG5000 [HuArgI (co)-PEG5000]-induced arginine depletion is selectively cytotoxic to human glioblastoma cells. J Neuro-Oncol 122(1):75\u201385. https:\/\/doi.org\/10.1007\/s11060-014-1698-5. Epub 2015 Jan 8","journal-title":"J Neuro-Oncol"},{"key":"883_CR14","doi-asserted-by":"publisher","unstructured":"Nasreddine G, El-Sibai M, Abi-Habib RJ (2019) Cytotoxicity of [HuArgI (co)-PEG5000]-induced arginine deprivation to ovarian Cancer cells is autophagy dependent. Investig New Drugs. https:\/\/doi.org\/10.1007\/s10637-019-00756-w","DOI":"10.1007\/s10637-019-00756-w"},{"issue":"3","key":"883_CR15","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1021\/cb900267j","volume":"5","author":"EM Stone","year":"2010","unstructured":"Stone EM, Glazer ES, Chantranupong L, Cherukuri P, Breece RM, Tierney DL, Curley SA, Iverson BL, Georgiou G (2010) Replacing Mn(2+) with co(2+) in human arginase i enhances cytotoxicity toward l-arginine auxotrophic cancer cell lines. ACS Chem Biol 5(3):333\u2013342","journal-title":"ACS Chem Biol"},{"key":"883_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.503","volume":"5","author":"Z Wang","year":"2014","unstructured":"Wang Z, Shi X, Li Y, Fan J, Zeng X, Xian Z, Wang Z, Sun Y, Wang S, Song P, Zhao S, Hu H, Ju D (2014) Blocking autophagy enhanced cytotoxicity induced by recombinant human arginase in triple-negative breast cancer cells. Cell Death Dis 5:e1563","journal-title":"Cell Death Dis"},{"issue":"30","key":"883_CR17","doi-asserted-by":"publisher","first-page":"7660","DOI":"10.1200\/JCO.2005.02.0933","volume":"23","author":"PA Ascierto","year":"2005","unstructured":"Ascierto PA, Scala S, Castello G, Daponte A, Simeone E, Ottaiano A, Beneduce G, De Rosa V, Izzo F, Melucci MT, Ensor CM, Prestayko AW, Holtsberg FW, Bomalaski JS, Clark MA, Savaraj N, Feun LG, Logan TF (2005) Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies. J Clin Oncol 23(30):7660\u20137668","journal-title":"J Clin Oncol"},{"issue":"5","key":"883_CR18","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.tranon.2015.07.001","volume":"8","author":"A Bekdash","year":"2015","unstructured":"Bekdash A, Darwish M, Timsah Z, Kassab E, Ghanem H, Najjar V, Ghosn M, Nasser S, El-Hajj H, Bazerbachi A, Liu S, Leppla SH, Frankel AE, Abi-Habib RJ (2015) Phospho-MEK1\/2 and uPAR expression determine sensitivity of AML blasts to a Urokinase-activated Anthrax lethal toxin (PrAgU2\/LF). Transl Oncol 8(5):347\u2013357","journal-title":"Transl Oncol"},{"issue":"1","key":"883_CR19","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1593\/tlo.12313","volume":"6","author":"E Kassab","year":"2013","unstructured":"Kassab E, Darwish M, Timsah Z, Liu S, Leppla SH, Frankel AE, Abi-Habib RJ (2013) Cytotoxicity of anthrax lethal toxin to human acute myeloid leukemia cells is nonapoptotic and dependent on extracellular signal-regulated kinase 1\/2 activity. Transl Oncol 6(1):25\u201332","journal-title":"Transl Oncol"},{"issue":"8","key":"883_CR20","doi-asserted-by":"publisher","first-page":"1950","DOI":"10.1002\/ijc.23723","volume":"123","author":"TL Bowles","year":"2008","unstructured":"Bowles TL, Kim R, Galante J, Parsons CM, Virudachalam S, Kung HJ, Bold RJ (2008) Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. Int J Cancer 123(8):1950\u20131955","journal-title":"Int J Cancer"},{"issue":"2","key":"883_CR21","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1158\/0008-5472.CAN-08-3157","volume":"69","author":"RH Kim","year":"2009","unstructured":"Kim RH, Coates JM, Bowles TL, McNerney GP, Sutcliffe J, Jung JU, Gandour-Edwards R, Chuang FY, Bold RJ, Kung HJ (2009) Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. Cancer Res 69(2):700\u2013708","journal-title":"Cancer Res"},{"key":"883_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2012.197","volume":"4","author":"N Syed","year":"2013","unstructured":"Syed N, Langer J, Janczar K, Singh P, Lo Nigro C, Lattanzio L, Coley HM, Hatzimichael E, Bomalaski J, Szlosarek P, Awad M, O'Neil K, Roncaroli F, Crook T (2013) Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma. Cell Death Dis 4:e458","journal-title":"Cell Death Dis"},{"issue":"10","key":"883_CR23","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.4161\/cc.20424","volume":"11","author":"RL Macintosh","year":"2012","unstructured":"Macintosh RL, Timpson P, Thorburn J, Anderson KI, Thorburn A, Ryan KM (2012) Inhibition of autophagy impairs tumor cell invasion in an organotypic model. Cell Cycle 11(10):2022\u20132029","journal-title":"Cell Cycle"},{"issue":"10","key":"883_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2016.232","volume":"7","author":"GR Bean","year":"2016","unstructured":"Bean GR, Kremer JC, Prudner BC, Schenone AD, Yao JC, Schultze MB, Chen DY, Tanas MR, Adkins DR, Bomalaski J, Rubin BP, Michel LS, Van Tine BA (2016) A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas. Cell Death Dis 7(10):e2406","journal-title":"Cell Death Dis"},{"issue":"20","key":"883_CR25","doi-asserted-by":"publisher","first-page":"8487","DOI":"10.1007\/s00253-015-6565-6","volume":"99","author":"C Lin","year":"2015","unstructured":"Lin C, Wang Z, Li L, He Y, Fan J, Liu Z, Zhao S, Ju D (2015) The role of autophagy in the cytotoxicity induced by recombinant human arginase in laryngeal squamous cell carcinoma. Appl Microbiol Biotechnol 99(20):8487\u20138494","journal-title":"Appl Microbiol Biotechnol"},{"key":"883_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2012.83","volume":"3","author":"B Delage","year":"2012","unstructured":"Delage B, Luong P, Maharaj L, O'Riain C, Syed N, Crook T, Hatzimichael E, Papoudou-Bai A, Mitchell TJ, Whittaker SJ, Cerio R, Gribben J, Lemoine N, Bomalaski J, Li CF, Joel S, Fitzgibbon J, Chen LT, Szlosarek PW (2012) Promoter methylation of argininosuccinate synthetase-1 sensitizes lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis 3:e342","journal-title":"Cell Death Dis"},{"issue":"39","key":"883_CR27","doi-asserted-by":"publisher","first-page":"14147","DOI":"10.1073\/pnas.1404171111","volume":"111","author":"CA Changou","year":"2014","unstructured":"Changou CA, Chen YR, Xing L, Yen Y, Chuang FY, Cheng RH, Bold RJ, Ann DK, Kung HJ (2014) Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage and chromatin autophagy. Proc Natl Acad Sci U S A 111(39):14147\u201314152","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Investigational New Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10637-019-00883-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10637-019-00883-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10637-019-00883-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T04:42:31Z","timestamp":1678509751000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10637-019-00883-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,10]]},"references-count":27,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,10]]}},"alternative-id":["883"],"URL":"https:\/\/doi.org\/10.1007\/s10637-019-00883-4","relation":{},"ISSN":["0167-6997","1573-0646"],"issn-type":[{"value":"0167-6997","type":"print"},{"value":"1573-0646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,10]]},"assertion":[{"value":"11 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 November 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"Author Nathalie Khalil declares that she has no conflict of interest. Author Ralph J. Abi-Habib declares that he has no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This article does not contain any studies with human participants or animals performed by any of the authors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"For this type of study, formal consent is not required.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}