Abstract
Although vitamin C (VC) has recently garnered interest as an alternative cancer therapy, its clinical effects remain controversial. It was recently reported using in vitro prostate cancer cell lines that excess extracellular iron (EEI) diminishes anti-cancer effects of VC, promoting the decomposition of hydrogen peroxide (H2O2) generated by VC. Here we demonstrated that EEI diminished the inhibitory effect of VC on the survival of K562 human leukemic cells in vitro, by reducing the amount of H2O2 and abrogating the apoptosis pathways induced by VC. In vivo, in the presence of EEI, the growth inhibitory effect of VC on K562 cells was completely abrogated; in fact, VC enhanced K562 cell growth. Reduction of EEI restored the apoptosis-inducing effect of VC in vitro and enhanced the growth inhibitory effect of VC in vivo. Further studies are warranted to investigate whether the combination of VC and iron depletion has similar effects in various other leukemic or cancer cells against which VC has been effective in previous experimental studies.
Highlights
The therapeutic use of vitamin C (VC) against cancer including hematologic malignancies is controversial
In the present study, using immunodeficient mice transplanted with the human chronic myeloid leukemia-derived leukemic K562 cell line, we demonstrated that the growth inhibitory effect of VC on K562 cells can be completely abolished by the simultaneous administration of iron, and that in the presence of excess iron, K562 cell growth is enhanced by VC in vivo
Since VC is the inhibitor of IκBα kinase β that phosphorylates IκB and activates NF-κB, it was suggested that excess iron inhibits the suppressive effects of VC against NF-κB activation and HIF-1α expression in K562 cells by inhibiting intracellular uptake of VC and promoting the phosphorylation of IκB. These results indicated that excess iron diminishes the inhibitory effect of VC on the survival of K562 cells by promoting the decomposition of H2O2 and abrogating the apoptosis pathways induced by VC in vitro
Summary
The therapeutic use of vitamin C (VC) against cancer including hematologic malignancies is controversial. The redox-active labile iron reacts with H2O2 generated by VC, and enters the cell to mediate Fenton chemistry, producing the hydroxyl radical (·OH) that causes oxidative damage to DNA and macromolecules in the cancer cells, suggesting that VC can induce cancer cell-specific toxicity[9]. It was demonstrated in colorectal cancer cells that VC selectively kills KRAS and BRAF mutant cells, increasing endogenous ROS which inhibits glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by both posttranslational modifications and nicotinamide adenine dinucleotide (NAD)+ depletion, leading to an energetic crisis and cell death[10]. These findings suggested that the anti-cancer effect of VC was overestimated in previous in vitro studies
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