Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs

Abstract

PurposeWhile 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.MethodsWe directly compare the effects of ascorbate (supplied as ‘Pascorbin® solution for injection’) and DHA on tumor cell viability, and determine IC50 values for various cell lines. At concentrations well below the IC50, 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.ResultsWe 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 H2O2 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 IC50 exerts anti-proliferative effects on tumor cells. Those are based on interference with the cell cycle, namely by inducing a G0/G1 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-010-1418-6) contains supplementary material, which is available to authorized users.

Hepatotoxicity of Pentavalent Antimonial Drug: Possible Role of Residual Sb(III) and Protective Effect of Ascorbic Acid

“…Surprisingly, AA was found to improve the antileishmanial efficacy of Glu. As a possible explanation, AA may reduce the intracellular thiol concentration of Leishmania parasite, as previously reported in multidrug-resistant tumor cells (21,22), turning the antimonial drug more active (44). One should also consider that AA may exert either an antioxidant or a pro-oxidant activity, depending on the concentration and experimental conditions (45).…”

“…Ascorbic acid (AA), known as vitamin C, is an important antioxidant and ROS scavenger which is associated to arsenicals in the treatment of cancer (19)(20)(21). Among its several benefits, AA can increase the cytotoxicity of As(III) against multidrug-resistant cells, presumably through reduction of glutathione intracellular concentration (22,23).…”

Effects of nutrients on matrix metalloproteinases in human T-lymphotropic virus type 1 positive and negative malignant T-lymphocytes

“…While the mechanism behind MMP-2 expression is mostly unknown (36), the functional activity of MMPs is known to be detained by tissue inhibitors of metalloproteinases (TIMPs) and to be impacted by reactive oxygen species (roS), where excess production of roS, in association with the myeloperoxidase enzyme, would eventually inactivate MMPs (37). Ascorbate has been shown to promote H 2 O 2 -mediated cell death (38,39) and a combination therapy of AA and vitamin k significantly decreased both the activity and protein expression of MMP-2 and MMP-9 while increasing the protein expression of TIMP-1 and TIMP-2 (40). As such, the high dose of AA possibly decreased the enzymatic activity of MMP-2 through the production of large amounts of roS or via an inductive effect on TIMPs.…”

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

“…Consistent with the microarray data, quantitative reverse transcriptasepolymerase chain reaction (RT-PCR) experiments examining RNA extracted from tumors following ascorbate treatment indicate decreased tRNA synthetase and translation initiation factor mRNAs compared with the levels in control mice. A different study described effects of pharmacological ascorbate on the cell cycle; 1 mM ascorbate treatment produced an increase in the number of DU-145 prostate carcinoma cells in the G 0 /G 1 phase (27). Others also reported cell cycle arrest at the G 1 phase in the murine melanoma line, B16F10, when cells were treated with ascorbate doses of 0.2 mM or less (30).…”