{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:00:02Z","timestamp":1791928802216,"version":"4.3.4"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,12,7]],"date-time":"2017-12-07T00:00:00Z","timestamp":1512604800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,12,7]],"date-time":"2017-12-07T00:00:00Z","timestamp":1512604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pancreatic cancer is among the most lethal cancers with poorly tolerated treatments. There is increasing interest in using high-dose intravenous ascorbate (IVC) in treating this disease partially because of its low toxicity. IVC bypasses bioavailability barriers of oral ingestion, provides pharmacological concentrations in tissues, and exhibits selective cytotoxic effects in cancer cells through peroxide formation. Here, we further revealed its anti-pancreatic cancer mechanisms and conducted a phase I\/IIa study to investigate pharmacokinetic interaction between IVC and gemcitabine. Pharmacological ascorbate induced cell death in pancreatic cancer cells with diverse mutational backgrounds. Pharmacological ascorbate depleted cellular NAD+ preferentially in cancer cells versus normal cells, leading to depletion of ATP and robustly increased \u03b1-tubulin acetylation in cancer cells. While ATP depletion led to cell death, over-acetylated tubulin led to inhibition of motility and mitosis. Collagen was increased, and cancer cell epithelial-mesenchymal transition (EMT) was inhibited, accompanied with inhibition in metastasis. IVC was safe in patients and showed the possibility to prolong patient survival. There was no interference to gemcitabine pharmacokinetics by IVC administration. Taken together, these data revealed a multi-targeting mechanism of pharmacological ascorbate\u2019s anti-cancer action, with minimal toxicity, and provided guidance to design larger definitive trials testing efficacy of IVC in treating advanced pancreatic cancer.<\/jats:p>","DOI":"10.1038\/s41598-017-17568-8","type":"journal-article","created":{"date-parts":[[2017,12,1]],"date-time":"2017-12-01T16:42:44Z","timestamp":1512146564000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":125,"title":["High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I\/IIa study"],"prefix":"10.1038","volume":"7","author":[{"given":"Kishore","family":"Polireddy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruochen","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Reed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Williamson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Christian","family":"Violet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Pessetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew K.","family":"Godwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Levine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne A.","family":"Drisko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,12,7]]},"reference":[{"key":"17568_CR1","unstructured":"American Cancer Society. 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Expert Rev Anticancer Ther \n                           10, 529\u2013540, https:\/\/doi.org\/10.1586\/era.10.21 (2010).","journal-title":"Expert Rev Anticancer Ther"},{"key":"17568_CR4","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/S1470-2045(10)70237-0","volume":"12","author":"R Kim","year":"2011","unstructured":"Kim, R. FOLFIRINOX: a new standard treatment for advanced pancreatic cancer? Lancet Oncol \n                           12, 8\u20139, https:\/\/doi.org\/10.1016\/S1470-2045(10)70237-0 (2011).","journal-title":"Lancet Oncol"},{"key":"17568_CR5","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","volume":"369","author":"DD Von Hoff","year":"2013","unstructured":"Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. 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Combination 5-fluorouracil, folinic acid and cisplatin (LV5FU2-CDDP) followed by gemcitabine or the reverse sequence in metastatic pancreatic cancer: final results of a randomised strategic phase III trial (FFCD 0301). Gut \n                           59, 1527\u20131534, https:\/\/doi.org\/10.1136\/gut.2010.216135 (2010).","journal-title":"Gut"},{"key":"17568_CR8","first-page":"96","volume":"12","author":"PE Oberstein","year":"2011","unstructured":"Oberstein, P. E. & Saif, M. W. First-line treatment for advanced pancreatic cancer. Highlights from the \u201c2011 ASCO Gastrointestinal Cancers Symposium\u201d. San Francisco, CA, USA. January 20\u201322, 2011. JOP \n                           12, 96\u2013100 (2011).","journal-title":"JOP"},{"key":"17568_CR9","doi-asserted-by":"publisher","first-page":"222ra218","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. Science translational medicine. \n                           6, 222ra218, https:\/\/doi.org\/10.1126\/scitranslmed.3007154 (2014).","journal-title":"Science translational medicine."},{"key":"17568_CR10","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1093\/annonc\/mdn377","volume":"19","author":"LJ Hoffer","year":"2008","unstructured":"Hoffer, L. J. et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol \n                           19, 1969\u20131974, https:\/\/doi.org\/10.1093\/annonc\/mdn377 (2008).","journal-title":"Ann Oncol"},{"key":"17568_CR11","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 \n                           7, e29794, https:\/\/doi.org\/10.1371\/journal.pone.0029794 (2012).","journal-title":"PLoS One"},{"key":"17568_CR12","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 \n                           71, 765\u2013775, https:\/\/doi.org\/10.1007\/s00280-013-2070-8 (2013).","journal-title":"Cancer Chemother Pharmacol"},{"key":"17568_CR13","doi-asserted-by":"publisher","unstructured":"Schoenfeld, J. D. et al. O2- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell, https:\/\/doi.org\/10.1016\/j.ccell.2017.02.018 (2017).","DOI":"10.1016\/j.ccell.2017.02.018"},{"key":"17568_CR14","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1126\/science.aaa5004","volume":"350","author":"J Yun","year":"2015","unstructured":"Yun, J. et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science \n                           350, 1391\u20131396, https:\/\/doi.org\/10.1126\/science.aaa5004 (2015).","journal-title":"Science"},{"key":"17568_CR15","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1126\/science.1164368","volume":"321","author":"S Jones","year":"2008","unstructured":"Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. 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