Journal article
Pharmacologic ascorbate resistant pancreatic cancer demonstrates enhanced metastatic potential
Redox biology, Vol.84, 103694
07/01/2025
DOI: 10.1016/j.redox.2025.103694
PMCID: PMC12158610
PMID: 40440794
Abstract
Pharmacological ascorbate (P-AscH, high-dose, intravenous, vitamin C), is a pro-drug that generates hydrogen peroxide (H2O2) and is being investigated as a neoadjuvant treatment for pancreatic adenocarcinoma (PDAC). In a randomized, phase II clinical trial, P-AscH demonstrated encouraging results in terms of efficacy and safety. However, some patients do not respond to P-AscH suggesting that resistance occurs in a subset of patients. The aims of this study were two-fold: first to characterize PDAC cells resistant to P-AscH, and second, determine if these alterations enhance metastatic potential. Resistance to P-AscH increased the ability to detoxify H2O2, altered redox metabolism and cell cycle regulation, however mechanisms to P-AscH resistance were different in the cell lines studied. Transcriptomic analysis demonstrated a significant enrichment of the epithelial-to-mesenchymal gene expression pattern in the cell lines studied, suggesting that upregulation of metastatic phenotypes occur during acquisition of resistance to P-AscH. Cells resistant to P-AscH demonstrated increased invasive potential, more aggressive tumor colonization, and higher abundance of circulating tumor cells in vivo. Our data support that resistance to oxidative stress enhances metastatic disease and indicates a potential route for PDAC to tolerate high levels of P-AscH and may explain why some patients do not respond to this treatment regimen.
Details
- Title: Subtitle
- Pharmacologic ascorbate resistant pancreatic cancer demonstrates enhanced metastatic potential
- Creators
- Amanda PopeBrianne O'LearyJuan Du - Radiation Oncology AssociatesGarry R Buettner - University of IowaMichael Henry - University of IowaJoseph J Cullen - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.84, 103694
- DOI
- 10.1016/j.redox.2025.103694
- PMID
- 40440794
- PMCID
- PMC12158610
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- ELSEVIER
- Grant note
- NIH: P01 217797, T32 CA78586, R01 CA263550 Carver College of Medicine, Holden Comprehensive Cancer CenterLowa City Veteran's Administration Medical CenterUniversity of Iowa Central Microscopy Research FacilityUniversity of Iowa Vice President for ResearchCarver College of Medicine
Funding in support through NIH grants: P01 217797, T32 CA78586, R01 CA263550.The data presented herein were obtained at the Flow Cytometry Facility, which is a Carver College of Medicine/Holden Comprehensive Cancer Center core research facility at the University of Iowa. The facility is funded through user fees and the generous financial support of the Carver College of Medicine, Holden Comprehensive Cancer Center, and Lowa City Veteran's Administration Medical Center. The authors would like to acknowledge use of the University of Iowa Central Microscopy Research Facility, a core resource supported by the University of Iowa Vice President for Research, and the Carver College of Medicine. The authors would like to thank the Free Radical and Radi-ation Biology core facilities for use of equipment.
- Language
- English
- Date published
- 07/01/2025
- Academic Unit
- Molecular Physiology and Biophysics; Surgery; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984825530602771
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