Pharmacological ascorbate radiosensitizes pancreatic cancer

Juan Du, John A. Cieslak, 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)3314-3326
Number of pages13
JournalCancer Research
Volume75
Issue number16
DOIs
StatePublished - Aug 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Pharmacological ascorbate radiosensitizes pancreatic cancer'. Together they form a unique fingerprint.

Cite this