Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs

Abstract

Vitamin C is an antioxidant vitamin that has been hypothesized to antagonize the effects of reactive oxygen species-generating antineoplastic drugs.

The therapeutic efficacy of the widely used antineoplastic drugs doxorubicin, cisplatin, vincristine, methotrexate, and imatinib were compared in leukemia (K562) and lymphoma (RL) cell lines with and without pretreatment with dehydroascorbic acid, the commonly transported form of vitamin C.

The effect of vitamin C on viability, clonogenicity, apoptosis, P-glycoprotein, reactive oxygen species (ROS), and mitochondrial membrane potential was determined.

Pretreatment with vitamin C caused a dose-dependent attenuation of cytotoxicity, as measured by trypan blue exclusion and colony formation after treatment with all antineoplastic agents tested.

Vitamin C given before doxorubicin treatment led to a substantial reduction of therapeutic efficacy in mice with RL cell-derived xenogeneic tumors. Vitamin C treatment led to a dose-dependent decrease in apoptosis in cells treated with the antineoplastic agents that was not due to up-regulation of P-glycoprotein or vitamin C retention modulated by antineoplastics. Vitamin C had only modest effects on intracellular ROS and a more general cytoprotective profile than N-acetylcysteine, suggesting a mechanism of action that is not mediated by ROS.

All antineoplastic agents tested caused mitochondrial membrane depolarization that was inhibited by vitamin C. These findings indicate that vitamin C given before mechanistically dissimilar antineoplastic agents antagonizes therapeutic efficacy in a model of human hematopoietic cancers by preserving mitochondrial membrane potential. These results support the hypothesis that vitamin C supplementation during cancer treatment may detrimentally affect therapeutic response.

Supplement Figure

Supplemental Figure 1: Vitamin C does not alter p-glycoprotein expression and vitamin C retention is independent of antineoplastic agent administration:

K562 and RL were treated with 500?M DHA (solid gray) to internal concentrations of 18 mM and 8.5 mM vitamin C, respectively, or vehicle alone (black line) and were then incubated for 48 hours under normal growth conditions. P-glycoprotein expression was determined with U1C2-A488 Pgp antibody by flow cytometry (A). Two separate experiments were conducted in triplicate and the results shown are the histograms of a representative experiment. Vitamin C retention after antineoplastic administration for 24 hours was measured by scintillation spectrometry normalized to percent of initial concentration (B). Two separate experiments were conducted in triplicate and the results shown represent the mean values and the standard deviations of a representative experiment.

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