Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer. Cancer Res 2015 Aug 15;75(16):3314-26
Date
06/18/2015Pubmed ID
26081808Pubmed Central ID
PMC4537815DOI
10.1158/0008-5472.CAN-14-1707Scopus ID
2-s2.0-84942893061 (requires institutional sign-in at Scopus site) 82 CitationsAbstract
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.
Author List
Du J, Cieslak JA 3rd, Welsh JL, Sibenaller ZA, Allen BG, Wagner BA, Kalen AL, Doskey CM, Strother RK, Button AM, Mott SL, Smith B, Tsai S, Mezhir J, Goswami PC, Spitz DR, Buettner GR, Cullen JJMESH terms used to index this publication - Major topics in bold
AnimalsAntioxidants
Ascorbic Acid
Cell Line
Cell Line, Tumor
Cell Survival
Chemoradiotherapy
DNA Damage
Dose-Response Relationship, Radiation
Glutathione
Glutathione Disulfide
Humans
Hydrogen Peroxide
Kaplan-Meier Estimate
Linear Models
Mice, Nude
Oxidative Stress
Pancreatic Neoplasms
Radiation, Ionizing
Radiation-Sensitizing Agents
Tumor Burden
Xenograft Model Antitumor Assays
