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Cancer Res. 2015 Aug 15;75(16):3314-26. doi: 10.1158/0008-5472.CAN-14-1707. Epub 2015 Jun 16.

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer.

Author information

1
Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa.
2
Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa.
3
Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa.
4
Holden Comprehensive Cancer Center, Iowa City, Iowa.
5
Medical College of Wisconsin, Milwaukee, Wisconsin.
6
Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa.
7
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.

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.

PMID:
26081808
PMCID:
PMC4537815
DOI:
10.1158/0008-5472.CAN-14-1707
[Indexed for MEDLINE]
Free PMC Article

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