Abstract
Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage. The brain tumor, glioblastoma multiforme (GBM), is very resistant to radiation; radiosensitizing GBM cells will improve survival of GBM patients. Here, we demonstrate that a single fraction (6 Gy) of radiation combined with a 1 h exposure to ascorbate (5 mM) sensitized murine glioma GL261 cells to radiation in survival and colony-forming assays in vitro. In addition, we report the effect of a single fraction (4.5 Gy) of whole brain radiation combined with daily intraperitoneal injections of ascorbate (1 mg/kg) in an intracranial GL261 glioma mouse model. Tumor-bearing C57BL/6 mice were divided into four groups: one group received a single dose of 4.5 Gy to the brain 8 days after tumor implantation, a second group received daily intraperitoneal injections of ascorbate (day 8–45) after implantation, a third group received both treatments and a fourth control group received no treatment. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant.
Highlights
The use of high doses of ascorbate for the treatment of cancer is highly controversial [reviewed by Ref. [1]]
We first tested the sensitivity of GL261 cells in vitro to a single exposure of different doses of radiation (Gy) (Figure 2A) and a 1 h exposure to different concentrations of ascorbate (AA) (Figure 2B)
We have previously shown that our glioblastoma multiforme (GBM) cell lines do not produce many DSB after a single exposure of 1 or 3 Gy
Summary
The use of high (pharmacological) doses of ascorbate for the treatment of cancer is highly controversial [reviewed by Ref. [1]]. The use of high (pharmacological) doses of ascorbate for the treatment of cancer is highly controversial [reviewed by Ref. Intravenous/intraperitoneal injection of high-dose ascorbate (0.5–1.25 g/kg in humans; 1–4 g/kg in mice) can bypass regulation to generate serum levels of 30 mM for about 2 h [4, 5]. Such high concentrations of ascorbate have been reported to generate extracellular hydrogen peroxide, in the acidic metal-rich environment of solid tumors [reviewed by Ref. The extracellular addition of catalase abrogates the pro-oxidant effect of high-dose ascorbate [6,7,8,9], verifying the role of extracellular hydrogen peroxide in its mechanism of action
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