Journal article
Pharmacological Ascorbate as an Adjuvant for Enhancing Radiation-Chemotherapy Responses in Gastric Adenocarcinoma
Radiation research, Vol.189(5), pp.456-465
05/2018
DOI: 10.1667/RR14978.1
PMCID: PMC6117840
PMID: 29547353
Abstract
Gastric adenocarcinoma most often presents at an advanced stage and overall five-year survival of ∼30%. Pharmacological ascorbate (high-dose IV ascorbate) has been proposed as a promising nontoxic adjuvant to standard radio-chemotherapies in several cancer types. In the current study, pharmacological ascorbate (0.5-2 m M) caused a dose-dependent decrease (70-85% at 2 m M) in clonogenic survival of gastric adenocarcinoma cells (AGS and MNK-45), but was relatively nontoxic to a small intestinal epithelial nonimmortalized human cell isolate (FHs 74 Int). The addition of pharmacological ascorbate (1 m M) to standard radio-chemotherapies [i.e., 5-FU (5 μ M); cisplatin (0.5 μ M); irinotecan (2.5 μ M); carboplatin (5 μ M); paclitaxel (2-4 n M); and X rays (1.8 Gy)] also potentiated gastric cancer clonogenic cell killing [additional decreases were noted with: ascorbate plus 5-FU/radiation (1%); ascorbate plus cisplatin/irinotecan (9-19%); and ascorbate plus paclitaxel/carboplatin (6-7%)]. The gastric cancer cell toxicity and chemosensitization seen with pharmacological ascorbate was dependent on H
O
and the presence of catalytic metal ions. In addition, pharmacological ascorbate dosing resulted in a concentration-dependent decrease (64% at 20 m M, P ≤ 0.0001) in cancer cell invasion and migration that was inhibited by catalase. Finally, pharmacological ascorbate significantly increased the overall survival of mice with gastric cancer xenografts when used in combination with paclitaxel, carboplatin and radiation ( P = 0.019). These results demonstrate that pharmacological ascorbate is selectively cytotoxic to gastric adenocarcinoma cells (relative to normal intestinal epithelial cells) by a mechanism involving H
O
and redox active metal ions. Furthermore, pharmacological ascorbate significantly enhances gastric cancer xenograft responses to radio-chemotherapy as well as inhibiting tumor cell migration and invasiveness. Overall, these results support the hypothesis that pharmacological ascorbate can be used as an adjuvant with standard-of-care radio-chemotherapies for the treatment of gastric adenocarcinomas.
Details
- Title: Subtitle
- Pharmacological Ascorbate as an Adjuvant for Enhancing Radiation-Chemotherapy Responses in Gastric Adenocarcinoma
- Creators
- Brianne R O'Leary - Departments of a SurgeryFrederick K Houwen - Departments of a SurgeryChase L Johnson - Departments of a SurgeryBryan G Allen - b Radiation OncologyJames J Mezhir - b Radiation OncologyDaniel J Berg - c Internal Medicine, Free Radical and Radiation Biology Program, The Holden Comprehensive Cancer Center at the University of Iowa College of Medicine, Iowa City, IowaJoseph J Cullen - d The Veterans Affairs Medical Center, Iowa City, IowaDouglas R Spitz - b Radiation Oncology
- Resource Type
- Journal article
- Publication Details
- Radiation research, Vol.189(5), pp.456-465
- DOI
- 10.1667/RR14978.1
- PMID
- 29547353
- PMCID
- PMC6117840
- NLM abbreviation
- Radiat Res
- ISSN
- 0033-7587
- eISSN
- 1938-5404
- Publisher
- United States
- Grant note
- P30 ES005605 / NIEHS NIH HHS T32 CA148062 / NCI NIH HHS T35 HL007485 / NHLBI NIH HHS I01 BX001318 / BLRD VA R01 CA184051 / NCI NIH HHS R01 CA182804 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
- Language
- English
- Date published
- 05/2018
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Surgery; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984047776202771
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