Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy

• Published in: Redox biology Vol. 10; no. C; pp. 274 - 284
• Main Authors: Doskey, Claire M., Buranasudja, Visarut, Wagner, Brett A., Wilkes, Justin G., Du, Juan, Cullen, Joseph J., Buettner, Garry R.
• Format: Journal Article
• Language: English
• Published: Elsevier 01.12.2016
• Subjects: Research Paper
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2016.10.010

Ascorbate (AscH − ) functions as a versatile reducing agent. At pharmacological doses (P-AscH − ; [plasma AscH − ] ≥≈20 mM), achievable through intravenous delivery, oxidation of P-AscH − can produce a high flux of H 2 O 2 in tumors. Catalase is the major enzyme for detoxifying high concentrations of H 2 O 2 . We hypothesize that sensitivity of tumor cells to P-AscH − compared to normal cells is due to their lower capacity to metabolize H 2 O 2 . Rate constants for removal of H 2 O 2 ( k cell ) and catalase activities were determined for 15 tumor and 10 normal cell lines of various tissue types. A differential in the capacity of cells to remove H 2 O 2 was revealed, with the average k cell for normal cells being twice that of tumor cells. The ED 50 (50% clonogenic survival) of P-AscH − correlated directly with k cell and catalase activity. Catalase activity could present a promising indicator of which tumors may respond to P-AscH − . • Ascorbate oxidizes in cell culture medium to generate a flux of H 2 O 2 . • The rate constants for removal of extracellular H 2 O 2 are on average 2-fold higher in normal cells than in cancer cells. • The ED 50 of high-dose ascorbate correlated with the ability of tumor cells to remove extracellular H 2 O 2 . • The response to pharmacological ascorbate in murine-models of pancreatic cancer paralleled the in vitro results. fx1