{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:13:18Z","timestamp":1792667598649,"version":"4.5.0"},"reference-count":51,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T00:00:00Z","timestamp":1603065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T00:00:00Z","timestamp":1603065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 CA217797"],"award-info":[{"award-number":["P01 CA217797"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CA148062"],"award-info":[{"award-number":["CA148062"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 GM0677954"],"award-info":[{"award-number":["T32 GM0677954"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA086862"],"award-info":[{"award-number":["P30CA086862"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 CA217797"],"award-info":[{"award-number":["P01 CA217797"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pharmacological ascorbate (P-AscH<jats:sup>\u2212<\/jats:sup>, high-dose, intravenous vitamin C) is cytotoxic to tumor cells in doses achievable in humans. Phase I studies in pancreatic cancer (PDAC) utilizing P-AscH<jats:sup>\u2212<\/jats:sup> have demonstrated increases in progression free survival, suggesting a reduction in metastatic disease burden. The purpose of this study was to determine the effects of P-AscH<jats:sup>\u2212<\/jats:sup> on metastatic PDAC. Several in vitro and in vivo mechanisms involved in PDAC metastases were investigated following treatment with P-AscH<jats:sup>\u2212<\/jats:sup>. Serum from PDAC patients in clinical trials with P-AscH<jats:sup>\u2212<\/jats:sup> were tested for the presence and quantity of circulating tumor cell-derived nucleases. P-AscH<jats:sup>\u2212<\/jats:sup> inhibited invasion, basement membrane degradation, decreased matrix metalloproteinase expression, as well as clonogenic survival and viability during exposure to fluid shear stress. In vivo<jats:italic>,<\/jats:italic> P-AscH<jats:sup>\u2212<\/jats:sup> significantly decreased formation of ascites, tumor burden over time, circulating tumor cells, and hepatic metastases. Both in vitro and in vivo findings were reversed with the addition of catalase suggesting that the effect of P-AscH<jats:sup>\u2212<\/jats:sup> on metastatic disease is mediated by hydrogen peroxide. Finally, P-AscH<jats:sup>\u2212<\/jats:sup> decreased CTC-derived nucleases in subjects with stage IV PDAC in a phase I clinical trial. We conclude that P-AscH<jats:sup>\u2212<\/jats:sup> attenuates the metastatic potential of PDAC and may prove to be effective for treating advanced disease.<\/jats:p>","DOI":"10.1038\/s41598-020-74806-2","type":"journal-article","created":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T10:09:45Z","timestamp":1603102185000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Pharmacological ascorbate inhibits pancreatic cancer metastases via a peroxide-mediated mechanism"],"prefix":"10.1038","volume":"10","author":[{"given":"Brianne R.","family":"O\u2019Leary","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S.","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devon L.","family":"Moose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Henry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Cullen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"key":"74806_CR1","unstructured":"Howlader, N., Noone, A., Krapcho, M., Miller, D., Brest, A., Yu, M., Ruhl, J., Tatalovich, Z., Mariotto, A., Lewis, D. R., Chen, H. S., Feuer, E. J. & Cronin, K. A. SEER Cancer Statistics Review, 1975\u20132016 (2018)."},{"key":"74806_CR2","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1038\/nature09515","volume":"467","author":"S Yachida","year":"2010","unstructured":"Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114\u20131117. https:\/\/doi.org\/10.1038\/nature09515 (2010).","journal-title":"Nature"},{"key":"74806_CR3","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.cell.2011.11.025","volume":"148","author":"AD Rhim","year":"2012","unstructured":"Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349\u2013361. https:\/\/doi.org\/10.1016\/j.cell.2011.11.025 (2012).","journal-title":"Cell"},{"key":"74806_CR4","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1158\/1078-0432.ccr-09-1713","volume":"16","author":"J Du","year":"2010","unstructured":"Du, J. et al. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 16, 509\u2013520. https:\/\/doi.org\/10.1158\/1078-0432.ccr-09-1713 (2010).","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"74806_CR5","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.freeradbiomed.2015.02.018","volume":"83","author":"JA Cieslak","year":"2015","unstructured":"Cieslak, J. A. et al. Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer. Free Radical Biol. Med. 83, 227\u2013237. https:\/\/doi.org\/10.1016\/j.freeradbiomed.2015.02.018 (2015).","journal-title":"Free Radical Biol. Med."},{"key":"74806_CR6","doi-asserted-by":"publisher","first-page":"6838","DOI":"10.1158\/0008-5472.can-18-1680","volume":"78","author":"MS Alexander","year":"2018","unstructured":"Alexander, M. S., Wilkes, J. G., Schroeder, S. R. & Buettner, G. R. Pharmacologic ascorbate reduces radiation-induced normal tissue toxicity and enhances tumor radiosensitization in pancreatic cancer. Cancer Res. 78, 6838\u20136851. https:\/\/doi.org\/10.1158\/0008-5472.can-18-1680 (2018).","journal-title":"Cancer Res."},{"key":"74806_CR7","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1007\/s00280-013-2070-8","volume":"71","author":"JL Welsh","year":"2013","unstructured":"Welsh, J. L. et al. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother. Pharmacol. 71, 765\u2013775. https:\/\/doi.org\/10.1007\/s00280-013-2070-8 (2013).","journal-title":"Cancer Chemother. Pharmacol."},{"key":"74806_CR8","doi-asserted-by":"publisher","first-page":"e29794","DOI":"10.1371\/journal.pone.0029794","volume":"7","author":"DA Monti","year":"2012","unstructured":"Monti, D. A. et al. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS ONE 7, e29794. https:\/\/doi.org\/10.1371\/journal.pone.0029794 (2012).","journal-title":"PLoS ONE"},{"key":"74806_CR9","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/nature15726","volume":"527","author":"E Piskounova","year":"2015","unstructured":"Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186\u2013191. https:\/\/doi.org\/10.1038\/nature15726 (2015).","journal-title":"Nature"},{"key":"74806_CR10","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nature16064","volume":"527","author":"X Zheng","year":"2015","unstructured":"Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525\u2013530. https:\/\/doi.org\/10.1038\/nature16064 (2015).","journal-title":"Nature"},{"key":"74806_CR11","doi-asserted-by":"publisher","first-page":"3864","DOI":"10.1016\/j.celrep.2020.02.080","volume":"30","author":"DL Moose","year":"2020","unstructured":"Moose, D. L. et al. Cancer cells resist mechanical destruction in circulation via RhoA\/actomyosin-dependent mechano-adaptation. Cell Rep. 30, 3864-3874.e3866. https:\/\/doi.org\/10.1016\/j.celrep.2020.02.080 (2020).","journal-title":"Cell Rep."},{"key":"74806_CR12","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.redox.2016.10.010","volume":"10","author":"CM Doskey","year":"2016","unstructured":"Doskey, C. M. et al. Tumor cells have decreased ability to metabolize H2O2: implications for pharmacological ascorbate in cancer therapy. Redox Biol. 10, 274\u2013284. https:\/\/doi.org\/10.1016\/j.redox.2016.10.010 (2016).","journal-title":"Redox Biol."},{"key":"74806_CR13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-19-3094","author":"AR Gibson","year":"2020","unstructured":"Gibson, A. R. et al. Dual oxidase-induced sustained generation of hydrogen peroxide contributes to pharmacological ascorbate-induced cytotoxicity. Can. Res. https:\/\/doi.org\/10.1158\/0008-5472.Can-19-3094 (2020).","journal-title":"Can. Res."},{"key":"74806_CR14","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/s0955-0674(96)80116-5","volume":"8","author":"CB Basbaum","year":"1996","unstructured":"Basbaum, C. B. & Werb, Z. Focalized proteolysis: spatial and temporal regulation of extracellular matrix degradation at the cell surface. Curr. Opin. Cell Biol. 8, 731\u2013738. https:\/\/doi.org\/10.1016\/s0955-0674(96)80116-5 (1996).","journal-title":"Curr. Opin. Cell Biol."},{"key":"74806_CR15","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.ceb.2008.01.005","volume":"20","author":"M Gimona","year":"2008","unstructured":"Gimona, M., Buccione, R., Courtneidge, S. A. & Linder, S. Assembly and biological role of podosomes and invadopodia. Curr. Opin. Cell Biol. 20, 235\u2013241. https:\/\/doi.org\/10.1016\/j.ceb.2008.01.005 (2008).","journal-title":"Curr. Opin. Cell Biol."},{"key":"74806_CR16","doi-asserted-by":"publisher","first-page":"e50973","DOI":"10.1371\/journal.pone.0050973","volume":"7","author":"JM Barnes","year":"2012","unstructured":"Barnes, J. M., Nauseef, J. T. & Henry, M. D. Resistance to fluid shear stress is a conserved biophysical property of malignant cells. PLoS ONE 7, e50973. https:\/\/doi.org\/10.1371\/journal.pone.0050973 (2012).","journal-title":"PLoS ONE"},{"key":"74806_CR17","doi-asserted-by":"publisher","first-page":"13604","DOI":"10.1073\/pnas.0506390102","volume":"102","author":"Q Chen","year":"2005","unstructured":"Chen, Q. et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc. Natl. Acad. Sci. U.S.A. 102, 13604\u201313609. https:\/\/doi.org\/10.1073\/pnas.0506390102 (2005).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"74806_CR18","doi-asserted-by":"publisher","first-page":"8749","DOI":"10.1073\/pnas.0702854104","volume":"104","author":"Q Chen","year":"2007","unstructured":"Chen, Q. et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl. Acad. Sci. U.S.A. 104, 8749\u20138754. https:\/\/doi.org\/10.1073\/pnas.0702854104 (2007).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"74806_CR19","doi-asserted-by":"publisher","first-page":"11105","DOI":"10.1073\/pnas.0804226105","volume":"105","author":"Q Chen","year":"2008","unstructured":"Chen, Q. et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. U.S.A. 105, 11105\u201311109. https:\/\/doi.org\/10.1073\/pnas.0804226105 (2008).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"74806_CR20","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1126\/scitranslmed.3007154","volume":"6","author":"Y Ma","year":"2014","unstructured":"Ma, Y. et al. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci. Transl. Med. 6, 222\u2013218. https:\/\/doi.org\/10.1126\/scitranslmed.3007154 (2014).","journal-title":"Sci. Transl. Med."},{"key":"74806_CR21","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1002\/mc.21891","volume":"52","author":"J Du","year":"2013","unstructured":"Du, J. et al. Regulation of pancreatic cancer growth by superoxide. Mol. Carcinog. 52, 555\u2013567. https:\/\/doi.org\/10.1002\/mc.21891 (2013).","journal-title":"Mol. Carcinog."},{"key":"74806_CR22","doi-asserted-by":"publisher","first-page":"17188","DOI":"10.1038\/s41598-017-17568-8","volume":"7","author":"K Polireddy","year":"2017","unstructured":"Polireddy, K. et al. High dose parenteral ascorbate inhibited pancreatic cancer growth and metastasis: mechanisms and a phase I\/IIa study. Sci. Rep. 7, 17188. https:\/\/doi.org\/10.1038\/s41598-017-17568-8 (2017).","journal-title":"Sci. Rep."},{"key":"74806_CR23","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1667\/rr14978.1","volume":"189","author":"BR O'Leary","year":"2018","unstructured":"O\u2019Leary, B. R. et al. Pharmacological ascorbate as an adjuvant for enhancing radiation-chemotherapy responses in gastric adenocarcinoma. Radiat. Res. 189, 456\u2013465. https:\/\/doi.org\/10.1667\/rr14978.1 (2018).","journal-title":"Radiat. Res."},{"key":"74806_CR24","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.1016\/j.biocel.2006.05.003","volume":"38","author":"M Gimona","year":"2006","unstructured":"Gimona, M. & Buccione, R. Adhesions that mediate invasion. Int. J. Biochem. Cell Biol. 38, 1875\u20131892. https:\/\/doi.org\/10.1016\/j.biocel.2006.05.003 (2006).","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"74806_CR25","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.ejcb.2005.09.005","volume":"85","author":"I Ayala","year":"2006","unstructured":"Ayala, I., Baldassarre, M., Caldieri, G. & Buccione, R. Invadopodia: a guided tour. Eur. J. Cell Biol. 85, 159\u2013164. https:\/\/doi.org\/10.1016\/j.ejcb.2005.09.005 (2006).","journal-title":"Eur. J. Cell Biol."},{"key":"74806_CR26","doi-asserted-by":"publisher","first-page":"3034","DOI":"10.1158\/0008-5472.Can-05-2177","volume":"66","author":"VV Artym","year":"2006","unstructured":"Artym, V. V., Zhang, Y., Seillier-Moiseiwitsch, F., Yamada, K. M. & Mueller, S. C. Dynamic interactions of cortactin and membrane type 1 matrix metalloproteinase at invadopodia: defining the stages of invadopodia formation and function. Can. Res. 66, 3034\u20133043. https:\/\/doi.org\/10.1158\/0008-5472.Can-05-2177 (2006).","journal-title":"Can. Res."},{"key":"74806_CR27","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.ejca.2016.03.081","volume":"62","author":"LH Schwartz","year":"2016","unstructured":"Schwartz, L. H. et al. RECIST 1.1-Update and clarification: from the RECIST committee. Eur. J. Cancer 62, 132\u2013137. https:\/\/doi.org\/10.1016\/j.ejca.2016.03.081 (2016).","journal-title":"Eur. J. Cancer"},{"key":"74806_CR28","doi-asserted-by":"publisher","first-page":"43464","DOI":"10.1038\/srep43464","volume":"7","author":"WT Yan","year":"2017","unstructured":"Yan, W. T. et al. Circulating tumor cell status monitors the treatment responses in breast cancer patients: a meta-analysis. Sci. Rep. 7, 43464. https:\/\/doi.org\/10.1038\/srep43464 (2017).","journal-title":"Sci. Rep."},{"key":"74806_CR29","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1245\/s10434-017-6290-8","volume":"25","author":"CM Court","year":"2018","unstructured":"Court, C. M. et al. Circulating tumor cells predict occult metastatic disease and prognosis in pancreatic cancer. Ann. Surg. Oncol. 25, 1000\u20131008. https:\/\/doi.org\/10.1245\/s10434-017-6290-8 (2018).","journal-title":"Ann. Surg. Oncol."},{"key":"74806_CR30","doi-asserted-by":"publisher","first-page":"2206","DOI":"10.3892\/ijo.2016.3747","volume":"49","author":"Y Hong","year":"2016","unstructured":"Hong, Y., Fang, F. & Zhang, Q. Circulating tumor cell clusters: what we know and what we expect (review). Int. J. Oncol. 49, 2206\u20132216. https:\/\/doi.org\/10.3892\/ijo.2016.3747 (2016).","journal-title":"Int. J. Oncol."},{"key":"74806_CR31","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/nrurol.2016.224","volume":"14","author":"MA Gorin","year":"2017","unstructured":"Gorin, M. A. et al. Circulating tumour cells as biomarkers of prostate, bladder, and kidney cancer. Nat. Rev. Urol. 14, 90\u201397. https:\/\/doi.org\/10.1038\/nrurol.2016.224 (2017).","journal-title":"Nat. Rev. Urol."},{"key":"74806_CR32","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/onc.2015.192","volume":"35","author":"K Pantel","year":"2016","unstructured":"Pantel, K. & Speicher, M. R. The biology of circulating tumor cells. Oncogene 35, 1216\u20131224. https:\/\/doi.org\/10.1038\/onc.2015.192 (2016).","journal-title":"Oncogene"},{"key":"74806_CR33","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nature08268","volume":"461","author":"ZT Schafer","year":"2009","unstructured":"Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109\u2013113. https:\/\/doi.org\/10.1038\/nature08268 (2009).","journal-title":"Nature"},{"key":"74806_CR34","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1007\/978-3-319-95294-9_11","volume":"1092","author":"BL Krog","year":"2018","unstructured":"Krog, B. L. & Henry, M. D. Biomechanics of the circulating tumor cell microenvironment. Adv. Exp. Med. Biol. 1092, 209\u2013233. https:\/\/doi.org\/10.1007\/978-3-319-95294-9_11 (2018).","journal-title":"Adv. Exp. Med. Biol."},{"key":"74806_CR35","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1007\/s12195-014-0357-4","volume":"7","author":"CG Scheitlin","year":"2014","unstructured":"Scheitlin, C. G., Nair, D. M., Crestanello, J. A., Zweier, J. L. & Alevriadou, B. R. Fluid mechanical forces and endothelial mitochondria: a bioengineering perspective. Cell Mol. Bioeng. 7, 483\u2013496. https:\/\/doi.org\/10.1007\/s12195-014-0357-4 (2014).","journal-title":"Cell Mol. Bioeng."},{"key":"74806_CR36","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/j.canlet.2016.12.001","volume":"388","author":"S Ma","year":"2017","unstructured":"Ma, S., Fu, A., Chiew, G. G. & Luo, K. Q. Hemodynamic shear stress stimulates migration and extravasation of tumor cells by elevating cellular oxidative level. Cancer Lett. 388, 239\u2013248. https:\/\/doi.org\/10.1016\/j.canlet.2016.12.001 (2017).","journal-title":"Cancer Lett."},{"key":"74806_CR37","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1056\/NEJMoa032295","volume":"350","author":"JP Neoptolemos","year":"2004","unstructured":"Neoptolemos, J. P. et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med. 350, 1200\u20131210. https:\/\/doi.org\/10.1056\/NEJMoa032295 (2004).","journal-title":"N. Engl. J. Med."},{"key":"74806_CR38","doi-asserted-by":"publisher","first-page":"4973","DOI":"10.1158\/1078-0432.Ccr-19-0197","volume":"25","author":"VP Groot","year":"2019","unstructured":"Groot, V. P. et al. Circulating tumor DNA as a clinical test in resected pancreatic cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 25, 4973\u20134984. https:\/\/doi.org\/10.1158\/1078-0432.Ccr-19-0197 (2019).","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"74806_CR39","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1053\/j.gastro.2018.09.022","volume":"156","author":"V Bernard","year":"2019","unstructured":"Bernard, V. et al. Circulating nucleic acids are associated with outcomes of patients with pancreatic cancer. Gastroenterology 156, 108-118.e104. https:\/\/doi.org\/10.1053\/j.gastro.2018.09.022 (2019).","journal-title":"Gastroenterology"},{"key":"74806_CR40","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.omtn.2017.08.004","volume":"8","author":"S Kruspe","year":"2017","unstructured":"Kruspe, S. et al. Rapid and sensitive detection of breast cancer cells in patient blood with nuclease-activated probe technology. Mol. Ther. Nucleic Acids 8, 542\u2013557. https:\/\/doi.org\/10.1016\/j.omtn.2017.08.004 (2017).","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"74806_CR41","doi-asserted-by":"publisher","first-page":"e90400","DOI":"10.1371\/journal.pone.0090400","volume":"9","author":"I Roy","year":"2014","unstructured":"Roy, I. et al. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS ONE 9, e90400. https:\/\/doi.org\/10.1371\/journal.pone.0090400 (2014).","journal-title":"PLoS ONE"},{"key":"74806_CR42","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1038\/nprot.2009.171","volume":"4","author":"MP Kim","year":"2009","unstructured":"Kim, M. P. et al. Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice. Nat. Protoc. 4, 1670\u20131680. https:\/\/doi.org\/10.1038\/nprot.2009.171 (2009).","journal-title":"Nat. Protoc."},{"key":"74806_CR43","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.redox.2017.08.017","volume":"14","author":"KE Brandt","year":"2018","unstructured":"Brandt, K. E. et al. Augmentation of intracellular iron using iron sucrose enhances the toxicity of pharmacological ascorbate in colon cancer cells. Redox Biol. 14, 82\u201387. https:\/\/doi.org\/10.1016\/j.redox.2017.08.017 (2018).","journal-title":"Redox Biol."},{"key":"74806_CR44","doi-asserted-by":"publisher","unstructured":"Heer, C. D. et al. Superoxide dismutase mimetic GC4419 enhances the oxidation of pharmacological ascorbate and its anticancer effects in an H(2)O(2)-dependent manner.https:\/\/doi.org\/10.3390\/antiox7010018 (2018).","DOI":"10.3390\/antiox7010018"},{"key":"74806_CR45","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1158\/1541-7786.Mcr-10-0475","volume":"9","author":"VP Muniz","year":"2011","unstructured":"Muniz, V. P. et al. The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis. Mol. Cancer Res. 9, 867\u2013877. https:\/\/doi.org\/10.1158\/1541-7786.Mcr-10-0475 (2011).","journal-title":"Mol. Cancer Res."},{"key":"74806_CR46","doi-asserted-by":"publisher","first-page":"e97","DOI":"10.14440\/jbm.2018.250","volume":"5","author":"MS Alexander","year":"2018","unstructured":"Alexander, M. S. et al. A model for the detection of pancreatic ductal adenocarcinoma circulating tumor cells. J. Biol. Methods 5, e97. https:\/\/doi.org\/10.14440\/jbm.2018.250 (2018).","journal-title":"J. Biol. Methods"},{"key":"74806_CR47","doi-asserted-by":"publisher","first-page":"e0132572","DOI":"10.1371\/journal.pone.0132572","volume":"10","author":"CM Doskey","year":"2015","unstructured":"Doskey, C. M., van \u2018t Erve, T. J., Wagner, B. A. & Buettner, G. R. Moles of a substance per cell is a highly informative dosing metric in cell culture. PLoS ONE 10, e0132572. https:\/\/doi.org\/10.1371\/journal.pone.0132572 (2015).","journal-title":"PLoS ONE"},{"key":"74806_CR48","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1002\/jcp.1041310308","volume":"131","author":"DR Spitz","year":"1987","unstructured":"Spitz, D. R., Dewey, W. C. & Li, G. C. Hydrogen peroxide or heat shock induces resistance to hydrogen peroxide in Chinese hamster fibroblasts. J. Cell Physiol. 131, 364\u2013373. https:\/\/doi.org\/10.1002\/jcp.1041310308 (1987).","journal-title":"J. Cell Physiol."},{"key":"74806_CR49","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1007\/978-1-59745-413-1_15","volume":"522","author":"VV Artym","year":"2009","unstructured":"Artym, V. V., Yamada, K. M. & Mueller, S. C. ECM degradation assays for analyzing local cell invasion. Methods Mol. Biol. 522, 211\u2013219. https:\/\/doi.org\/10.1007\/978-1-59745-413-1_15 (2009).","journal-title":"Methods Mol. Biol."},{"key":"74806_CR50","doi-asserted-by":"publisher","DOI":"10.3791\/51677","author":"KC Soares","year":"2014","unstructured":"Soares, K. C. et al. A preclinical murine model of hepatic metastases. J. Vis. Exp. https:\/\/doi.org\/10.3791\/51677 (2014).","journal-title":"J. Vis. Exp."},{"key":"74806_CR51","doi-asserted-by":"publisher","first-page":"3314","DOI":"10.1158\/0008-5472.can-14-1707","volume":"75","author":"J Du","year":"2015","unstructured":"Du, J. et al. Pharmacological ascorbate radiosensitizes pancreatic cancer. Can. Res. 75, 3314\u20133326. https:\/\/doi.org\/10.1158\/0008-5472.can-14-1707 (2015).","journal-title":"Can. Res."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-74806-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-74806-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-74806-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T21:45:56Z","timestamp":1670363156000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-74806-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,19]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["74806"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-74806-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,19]]},"assertion":[{"value":"23 April 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17649"}}