{"doi":"10.1016/j.redox.2025.103694","title":"Pharmacologic ascorbate resistant pancreatic cancer demonstrates enhanced metastatic potential","abstract":"Pharmacological ascorbate (P-AscH, high-dose, intravenous, vitamin C), is a pro-drug that generates hydrogen peroxide (H 2 O 2 ) 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 H 2 O 2 , 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.","journal":"Redox Biology","year":2025,"id":532407,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":408977,"name":"Brianne R. O’Leary","orcid":"0000-0001-7431-1141","position":1,"is_corresponding":false},{"id":1413576,"name":"Juan Du","orcid":"0000-0002-7978-0665","position":2,"is_corresponding":false},{"id":297603,"name":"Garry R. Buettner","orcid":"0000-0002-5594-1903","position":3,"is_corresponding":false},{"id":275281,"name":"Michael D. Henry","orcid":"0000-0002-7871-245X","position":4,"is_corresponding":false},{"id":401827,"name":"Joseph J. Cullen","orcid":"0000-0002-2222-1328","position":5,"is_corresponding":false},{"id":926021,"name":"Amanda N. Pope","orcid":"0000-0002-8410-2367","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:51:23.237536Z","pmid":"40440794","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}