Abstract
Ascorbate is a pro-oxidant that generates hydrogen peroxide–dependent cytotoxity in cancer cells without adversely affecting normal cells. To determine the mechanistic basis for this phenotype, we selected Burkitt lymphoma cells resistant to ascorbate (JLPR cells) and their ascorbate-sensitive parental cells (JLPS cells). Compared with JLPS cells, the increased glucose uptake in JLPR cells (with upregulated glucose transporters, increased antioxidant enzyme activity, and altered cell cycling) conferred ascorbate–induced cytotoxicity and resistance. Transcriptomic profiles and function pathway analysis identified differentially expressed gene signatures for JLPR cells and JLPS cells, which differential expression levels of five genes (ATF5, CD79B, MHC, Myosin, and SAP18) in ascorbate-resistant cells were related to phosphoinositide 3 kinase, cdc42, DNA methylation and transcriptional repression, polyamine regulation, and integrin-linked kinase signaling pathways. These results suggested that coordinated changes occurred in JLPR cells to enable their survival when exposed to the cytotoxic pro-oxidant stress elicited by pharmacologic ascorbate treatment.
Highlights
Ascorbate (Vitamin C) is a nutrient essential to the biosynthesis of collagen and L-carnitine and the conversion of dopamine to norepinephrine [1]
Using the MTT assay, we found that JLPR cells were highly resistant to ascorbate and H2O2 at IC50 values of 1250 μM and 32 μM, respectively (Figure 1A, Figure 1B, and Table 1)
JLPS cells incubated with 1 mM docosahexanoic acid (DHA) for 1 h had a similar amount of ascorbate as JLPR cells did (Figure 1C)
Summary
Ascorbate (Vitamin C) is a nutrient essential to the biosynthesis of collagen and L-carnitine and the conversion of dopamine to norepinephrine [1]. In vitro studies have shown that pharmacologic ascorbate is effective in a large panel of tumor cell lines [8, 9] and that increasing tumor cells’ generation of hydrogen peroxide (H2O2) might be used to induce ascorbatespecific cytotoxicity [10]. Pharmacologic ascorbate has been found to mediate the mitochondrial release of cytochrome C, which leads to H2O2-mediated activation of the caspase cascade and apoptotic process and thence to a significant decrease in the growth rate of some solid tumors [11,12,13,14]. Herst investigated that 5 mM ascorbate in combination with radiation killed more glioblastoma multiforme primary cells by increasing oxidative DNA damage than either treatment alone [15]. The effect of high doses of intravenous ascorbate in the treatment of cancer has been controversial there is growing evidence that intravenous high-dose ascorbate has been found to improve the health-related quality of life of terminal cancer patients [16,17]
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