Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer

Juan Du; John A Cieslak III; Jessemae L Welsh; Zita A Sibenaller; Bryan G Allen; Brett A Wagner; Amanda L Kalen; Claire M Doskey; Robert K Strother; Anna M Button; Sarah L Mott; Brian Smith; Susan Tsai; James Mezhir; Prabhat C Goswami; Douglas R Spitz; Garry R Buettner; Joseph J Cullen

doi:10.1158/0008-5472.can-14-1707

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Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer

Journal article

Open access

Peer reviewed

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer

Juan Du, John A Cieslak III, Jessemae L Welsh, Zita A Sibenaller, Bryan G Allen, Brett A Wagner, Amanda L Kalen, Claire M Doskey, Robert K Strother, Anna M Button, …

Cancer research (Chicago, Ill.), Vol.75(16), pp.3314-3326

08/15/2015

DOI: 10.1158/0008-5472.can-14-1707

PMCID: PMC4537815

PMID: 26081808

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Abstract

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

Pancreatic Neoplasms - metabolism

Glutathione - metabolism

Tumor Burden - radiation effects

Humans

Cell Survival - genetics

Glutathione Disulfide - metabolism

Chemoradiotherapy

Tumor Burden - genetics

Oxidative Stress - radiation effects

Radiation, Ionizing

Cell Line

Cell Survival - drug effects

Radiation-Sensitizing Agents - pharmacology

Kaplan-Meier Estimate

Linear Models

Pancreatic Neoplasms - genetics

Antioxidants - pharmacology

Cell Survival - radiation effects

Hydrogen Peroxide - metabolism

Xenograft Model Antitumor Assays

Animals

Tumor Burden - drug effects

Mice, Nude

Ascorbic Acid - pharmacology

Cell Line, Tumor

DNA Damage

Oxidative Stress - drug effects

Dose-Response Relationship, Radiation

Pancreatic Neoplasms - therapy

Details

Title: Subtitle: Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer
Creators: Juan Du - Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa
John A Cieslak III - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa
Jessemae L Welsh - Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa
Zita A Sibenaller - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa
Bryan G Allen - Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa
Brett A Wagner - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa
Amanda L Kalen - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa
Claire M Doskey - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa
Robert K Strother - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa
Anna M Button - Holden Comprehensive Cancer Center, Iowa City, Iowa
Sarah L Mott - Holden Comprehensive Cancer Center, Iowa City, Iowa
Brian Smith - Holden Comprehensive Cancer Center, Iowa City, Iowa
Susan Tsai - Medical College of Wisconsin, Milwaukee, Wisconsin
James Mezhir - Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa
Prabhat C Goswami - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa
Douglas R Spitz - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa
Garry R Buettner - Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa
Joseph J Cullen - Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa. Veterans Affairs Medical Center, Iowa City, Iowa. joseph-cullen@uiowa.edu
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.75(16), pp.3314-3326
DOI: 10.1158/0008-5472.can-14-1707
PMID: 26081808
PMCID: PMC4537815
NLM abbreviation: Cancer Res
ISSN: 1538-7445
eISSN: 1538-7445
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS T32 CA078586 / NCI NIH HHS T32 CA148062 / NCI NIH HHS T35 HL007485 / NHLBI NIH HHS P42 ES013661 / NIEHS NIH HHS I01 BX001318 / BLRD VA R01 CA184051 / NCI NIH HHS R01 CA182804 / NCI NIH HHS R01 CA111365 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA169046 / NCI NIH HHS
Language: English
Date published: 08/15/2015
Academic Unit: Pathology; Biostatistics; Surgery; Radiation Oncology; Holden Comprehensive Cancer Center
Record Identifier: 9983997445402771

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