Pharmacological Ascorbate as an Adjuvant for Enhancing Radiation-Chemotherapy Responses in Gastric Adenocarcinoma

• Published in: Radiation research 2018-05, Vol.189 (5), p.456-465
• Main Authors: O'Leary, Brianne R., Houwen, Frederick K., Johnson, Chase L., Allen, Bryan G., Mezhir, James J., Berg, Daniel J., Cullen, Joseph J., Spitz, Douglas R.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - pathology; Adenocarcinoma - therapy; Animals; Ascorbic Acid - pharmacology; Ascorbic Acid - therapeutic use; Cell Line, Tumor; Chemoradiotherapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Synergism; Female; Humans; Mice; REGULAR ARTICLES; Stomach Neoplasms - pathology; Stomach Neoplasms - therapy; Xenograft Model Antitumor Assays
• ISSN: 0033-7587; 1938-5404
• DOI: 10.1667/RR14978.1

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 mM) caused a dose-dependent decrease (70–85% at 2 mM) 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 mM) to standard radio-chemotherapies [i.e., 5-FU (5 μM); cisplatin (0.5 μM); irinotecan (2.5 μM); carboplatin (5 μM); paclitaxel (2–4 nM); 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 H2O2 and the presence of catalytic metal ions. In addition, pharmacological ascorbate dosing resulted in a concentration-dependent decrease (64% at 20 mM, 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 H2O2 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.