Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate
high dose IV vitamin C shown to be treatment option in Cancer. Granted in a mouse study, but high dose IV vitamin C shown to decrease growth rates of ovarian, pancreatic, and glioblastoma cancers.
This study found a pro oxidant effect of the addition of 5 grams of IV vitamin C with EDTA chelation. As dosing of IV vitamin C goes, 5 grams is quite small. Vitamin C has been shown to have varying effects (pro oxidant versus antioxidant) dictated by the dosage. One wonders if higher dosing IV vitamin C provides antioxidant effects?
Nice study that reveals the pharmacologic mechanism of vitamin C as a pro-oxidant in cancer cells. Obviously, this effect is opposite that found blood. In this study they looked at high dose IV vitamin C in the treatment of ovarian, pancreatic, and glioblastoma cancer. Treatment was beneficial and well tolerated.
An extensive panel of 43 tumor and 5 normal cell lines were exposed to ascorbate in vitro for ≤2 h to mimic clinical pharmacokinetics
effective concentration that decreased survival 50% (EC50) was determined. EC50 was <10 mM for 75% of tumor cells tested, whereas cytotoxicity was not evident in normal cells with >20 mM ascorbate
The addition of catalase to the medium ameliorated death of ovarian carcinoma (Ovcar5), pancreatic carcinoma (Pan02), and glioblastoma (9L) cells exposed to 10 mM ascorbate (1 h), indicating cytotoxicity was mediated by H2O2
A treatment dose of 4 g ascorbate/kg body weight either once or twice daily did not produce any discernible adverse effects
Xenograft experiments showed that parenteral ascorbate as the only treatment significantly decreased both tumor growth and weight by 41–53%
Peak plasma concentrations of ascorbate approached 30 mM
Pharmacologic concentrations of ascorbate decreased tumor volumes 41–53% in diverse cancer types known for both their aggressive growth and limited treatment options.
Our findings showed that pharmacologic ascorbic acid concentrations were cytotoxic to many types of cancer cells in vitro (Fig. 1A) and significantly impeded tumor progression in vivo without toxicity to normal tissues
The amelioration of ascorbate cytotoxicity in vitro by the addition of catalase was consistent among sensitive cancer cells (Fig. 1B) and points unambiguously to H2O2 generation in the extracellular medium
the current in vivo data support that pharmacologic ascorbate concentrations, which can readily be achieved in humans (Fig. 3E), diminished growth of several aggressive cancer types in mice (Fig. 2) without causing apparent adverse effects.
These intratumoral H2O2 concentrations of >125 μM persisted for >3 h after ascorbate administration
The data show that pharmacologic ascorbate concentrations produced Asc•− selectively in extracellular fluid compared with blood and that H2O2 formation occurred when Asc•− concentrations were >100 nM in extracellular fluid.
These data validate the hypothesis that ascorbate is a prodrug for selective delivery of reactive species to the extravascular space
pharmacologic ascorbate as a prooxidant drug for therapeutic use.
Recently we reported that pharmacologic ascorbic acid concentrations produced H2O2 concentrations of ≥25 μM, causing cancer cell death in vitro
We found that H2O2 concentrations generated in vivo were those that caused cancer cell death in vitro
When ascorbate was given parenterally, Asc•−, the product of a loss of one electron from ascorbate, was detected preferentially in extracellular fluid compared with blood
Asc•− generation in extracellular fluid depended on the ascorbate dose and the resulting concentrations
With i.v. administration of ascorbate, Asc•− concentrations were as much as 12-fold greater in extracellular fluid compared to blood and approached 250 nM
In blood, such Asc•− concentrations were never produced and were always <50 nM
These data are all consistent with the hypothesis that pharmacologic ascorbate concentrations in vivo serve as a prodrug for selective delivery of H2O2 to the extracellular space
After oral ingestion, control of intracellular and extracellular ascorbate concentrations is mediated by three mechanisms: intestinal absorption, tissue transport, and renal reabsorption
intestinal absorption, or bioavailability, declines at doses >200 mg
also at ≈60 μM, renal reabsorption approaches saturation, and excess ascorbate is excreted in urine
Parenteral administration bypasses tight control
When tight control is bypassed, H2O2 forms in the extracellular space
in vivo validation of ascorbate as a prodrug for selective H2O2 formation
Temporarily bypassing tight control with parenteral administration of ascorbate allows H2O2 to form in discrete time periods only, decreasing likelihood of harm, and provides a pharmacologic basis for therapeutic use of i.v. ascorbate
H2O2 formation results in selective cytotoxicity
Tumor cells are killed with exposure to H2O2 for ≤30 min
In vitro, killing is mediated by H2O2 rather than Asc•−
In addition to cancer treatment, another potential therapeutic use is for treatment of infections. H2O2 concentrations of 25–50 μM are bacteriostatic