Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs.
OBJECTIVE
While the benefits of ascorbic acid (vitamin C, ascorbate) as an essential nutrient are well established, its effects on tumor cells and in tumor treatment are controversial. In particular, conflicting data exist whether ascorbate may increase the cytotoxic effects of antineoplastic drugs or may rather exert adverse effects on drug sensitivity during cancer treatment. Findings are further obscured regarding the distinction between ascorbate and dehydroascorbate (DHA). Thus, the purpose of this study was to evaluate and directly compare the cytotoxic efficacy of ascorbate compared to DHA, and to analyse if ascorbate at pharmacological concentrations affects the efficacy of antineoplastic agents in prostate carcinoma cells.


METHODS
We directly compare the effects of ascorbate (supplied as 'Pascorbin solution for injection') and DHA on tumor cell viability, and determine IC(50) values for various cell lines. At concentrations well below the IC(50), ascorbate effects on cell proliferation and cell cycle are analysed. We furthermore determine changes in cellular sensitivity towards various cytostatic drugs upon pre-treatment of cells with ascorbate.


RESULTS
We demonstrate higher therapeutic efficacy of ascorbate over DHA in various cell lines, independent of cell line-specific differences in ascorbate sensitivity, and identify the extracellular generation of H(2)O(2) as critical mechanism of ascorbate action. We furthermore show that, in addition to pro-apoptotic effects described previously, ascorbate treatment already at concentrations well below the IC(50) exerts anti-proliferative effects on tumor cells. Those are based on interference with the cell cycle, namely by inducing a G(0)/G(1) arrest. Pre-treatment of tumor cells with ascorbate leads to increased cellular sensitivity towards Docetaxel, Epirubicin, Irinotecan and 5-FU, but not towards Oxaliplatin and Vinorelbin. For Docetaxel and 5-FU, a linear correlation between this sensitizing effect and the ascorbate dosage is observed.


CONCLUSIONS
The redox-active form of vitamin C, ascorbate, shows therapeutic efficacy in tumor cells. These antitumor effects of ascorbate are mainly based on its extracellular action and, in addition to the induction of apoptosis, also include an anti-proliferative effect by inducing cell cycle arrest. Furthermore, ascorbate treatment specifically enhances the cytostatic potency of certain chemotherapeutics, which implicates therapeutic benefit during tumor treatment.
Frömberg
Anja
A
Institute of Pharmacology, Faculty of Medicine, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, 35032 Marburg, Germany.
Gutsch
Daniela
D
Schulze
Daniel
D
Vollbracht
Claudia
C
Weiss
Gabriele
G
Czubayko
Frank
F
Aigner
Achim
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003683:Dehydroascorbic Acid / Q000494:pharmacology; D000077143:Docetaxel; D004357:Drug Synergism; D015251:Epirubicin / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D008297:Male; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D011471:Prostatic Neoplasms; D043823:Taxoids / Q000494:pharmacology; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D043823:Taxoids; D000077150:Oxaliplatin; D000077143:Docetaxel; D015251:Epirubicin; D014747:Vinblastine; D000077146:Irinotecan; D001205:Ascorbic Acid; D000077235:Vinorelbine; D002166:Camptothecin; D003683:Dehydroascorbic Acid