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Your Environment. Your Health.

Publication Detail

Title: Pharmacologic Ascorbate Primes Pancreatic Cancer Cells for Death by Rewiring Cellular Energetics and Inducing DNA Damage.

Authors: Buranasudja, Visarut; Doskey, Claire M; Gibson, Adrienne R; Wagner, Brett A; Du, Juan; Gordon, David J; Koppenhafer, Stacia L; Cullen, Joseph J; Buettner, Garry R

Published In Mol Cancer Res, (2019 10)

Abstract: The clinical potential of pharmacologic ascorbate (P-AscH-; intravenous delivery achieving mmol/L concentrations in blood) as an adjuvant in cancer therapy is being reevaluated. At mmol/L concentrations, P-AscH- is thought to exhibit anticancer activity via generation of a flux of H2O2 in tumors, which leads to oxidative distress. Here, we use cell culture models of pancreatic cancer to examine the effects of P-AscH- on DNA damage, and downstream consequences, including changes in bioenergetics. We have found that the high flux of H2O2 produced by P-AscH- induces DNA damage. In response to this DNA damage, we observed that PARP1 is hyperactivated. Using our unique absolute quantitation, we found that P-AscH- mediated the overactivation of PARP1, which results in consumption of NAD+, and subsequently depletion of ATP leading to mitotic cell death. We have also found that Chk1 plays a major role in the maintenance of genomic integrity following treatment with P-AscH-. Hyperactivation of PARP1 and DNA repair are ATP-consuming processes. Using a Seahorse XF96 analyzer, we demonstrated that the severe decrease in ATP after challenging with P-AscH- is because of increased demand, not changes in the rate of production. Genetic deletion and pharmacologic inhibition of PARP1 preserved both NAD+ and ATP; however, the toxicity of P-AscH- remained. These data indicate that disruption of bioenergetics is a secondary factor in the toxicity of P-AscH-; damage to DNA appears to be the primary factor. IMPLICATIONS: Efforts to leverage P-AscH- in cancer therapy should first focus on DNA damage.

PubMed ID: 31337671 Exiting the NIEHS site

MeSH Terms: Animals; Ascorbic Acid/pharmacology*; Carcinoma, Pancreatic Ductal/drug therapy*; Carcinoma, Pancreatic Ductal/genetics; Carcinoma, Pancreatic Ductal/metabolism; Carcinoma, Pancreatic Ductal/pathology; Cell Line, Tumor; DNA Damage*; Humans; Hydrogen Peroxide/metabolism; Mice; Mice, Nude; Pancreatic Neoplasms/drug therapy*; Pancreatic Neoplasms/genetics; Pancreatic Neoplasms/metabolism; Pancreatic Neoplasms/pathology; Poly (ADP-Ribose) Polymerase-1/metabolism; Transfection; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

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