Vitamin C and Cancer – more good news

Br J Cancer. 2010 Mar 23. [Epub ahead of print]

alpha-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate.

Tomasetti M, Strafella E, Staffolani S, Santarelli L, Neuzil J, Guerrieri R.

Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona 60020, Italy.


Background:A strategy to reduce the secondary effects of anti-cancer agents is to potentiate the therapeutic effect by their combination. A combination of vitamin K3 (VK3) and ascorbic acid (AA) exhibited an anti-cancer synergistic effect, associated with extracellular production of H(2)O(2) that promoted cell death.Methods:The redox-silent vitamin E analogue alpha-tocopheryl succinate (alpha-TOS) was used in combination with VK3 and AA to evaluate their effect on prostate cancer cells.Results:Prostate cancer cells were sensitive to alpha-TOS and VK3 treatment, but resistant to AA upto 3.2 mM. When combined, a synergistic effect was found for VK3-AA, whereas alpha-TOS-VK3 and alpha-TOS-AA combination showed an antagonist and additive effect, respectively. However, sub-lethal doses of AA-VK3 combination combined with a sub-toxic dose of alpha-TOS showed to induce efficient cell death that resembles autoschizis. Associated with this cell demise, lipid peroxidation, DNA damage, cytoskeleton alteration, lysosomal-mitochondrial perturbation, and release of cytochrome c without caspase activation were observed. Inhibition of lysosomal proteases did not attenuate cell death induced by the combined agents. Furthermore, cell deaths by apoptosis and autoschizis were detected.Conclusion:These finding support the emerging idea that synergistic combinations of some agents can overcome toxicity and other side-effects associated with high doses of single drugs creating the opportunity for therapeutically relevant selectivity.British Journal of Cancer advance online publication, 23 March 2010; doi:10.1038/sj.bjc.6605617

PMID: 20332775 [PubMed – as supplied by publisher]

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Cancer Chemother Pharmacol. 2010 Mar 6. [Epub ahead of print]

The antioxidant ascorbic acid mobilizes nuclear copper leading to a prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer.

Ullah MF, Khan HY, Zubair H, Shamim U, Hadi SM.

Department of Biochemistry, Faculty of Life Sciences, AMU, Aligarh, UP, 202002, India.


PURPOSE: Ascorbic acid is an essential micronutrient and is considered to have an antioxidant function in living systems. For the past several decades, ascorbic acid has been the subject of considerable interest as an anticancer agent. Several studies have shown that ascorbic acid is cytotoxic to a variety of cancer cells, whereas normal cells are relatively resistant to such cytotoxic action. In this study, we propose a putative molecular mechanism that accounts for the preferential cytotoxicity of ascorbic acid against cancer cells. METHODS: Standard and lysed version of alkaline single-cell gel electrophoresis (Comet assay); ferrous oxidation-xylenol orange (FOX) assay. RESULTS: We show that ascorbic acid acts as a prooxidant and leads to oxidative DNA breakage in lymphocytes and lymphocyte nuclei. Scavengers of reactive oxygen species were able to inhibit ascorbic acid-induced DNA breakage, suggesting the involvement of reactive oxygen species in this reaction. We further show that such DNA breakage is inhibited by both iron and copper chelators in cells, whereas in nuclei, similar inhibition was achieved only by copper chelators, indicating an important role of chromatin-bound copper in the prooxidant cellular DNA breakage by ascorbic acid. CONCLUSION: We propose that the copper-dependent cellular redox status is an important element in the cytotoxic action of ascorbic acid against cancer cells. It is well established that cellular copper levels are considerably elevated in various malignancies. Therefore, cancer cells may be more subject to electron transfer between copper and ascorbate to generate reactive oxygen species. In light of these observations and those in literature, in this paper we explain that the preferential cytotoxicity of ascorbic acid against cancer cells is the result of elevated copper levels in such cells. Further, this study identifies nuclear copper as a novel molecular target for cytotoxic action of ascorbic acid, which has implications for its chemotherapeutic properties against cancer.

PMID: 20213077 [PubMed – as supplied by publisher]

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Biochem Biophys Res Commun. 2010 Apr 2;394(2):249-53. Epub 2010 Feb 19.

High dose of ascorbic acid induces cell death in mesothelioma cells.

Takemura Y, Satoh M, Satoh K, Hamada H, Sekido Y, Kubota S.

Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.


Malignant mesothelioma is an asbestos-related fatal disease with no effective cure. Recently, high dose of ascorbate in cancer treatment has been reexamined. We studied whether high dose of ascorbic acid induced cell death of four human mesothelioma cell lines. High dose of ascorbic acid induced cell death of all mesothelioma cell lines in a dose-dependent manner. We further clarified the cell killing mechanism that ascorbic acid induced reactive oxygen species and impaired mitochondrial membrane potential. In vivo experiment, intravenous administration of ascorbic acid significantly decreased the growth rate of mesothelioma tumor inoculated in mice. These data suggest that ascorbic acid may have benefits for patients with mesothelioma. 2010 Elsevier Inc. All rights reserved.

PMID: 20171954 [PubMed – in process]

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J Angiogenes Res. 2010 Jan 18;2:2.

Ascorbate inhibition of angiogenesis in aortic rings ex vivo and subcutaneous Matrigel plugs in vivo.

Mikirova NA, Casciari JJ, Riordan NH.

Bio-Communications Research Institute, Wichita, Kansas, USA.


BACKGROUND: Angiogenesis is critical to tumor growth and is therefore a potential target for cancer therapy. As many current inhibitors of angiogenesis exhibit host toxicity, natural alternatives are needed. At millimolar concentrations, ascorbate (vitamin C) inhibits migration and tubule formation by mature endothelial cells and endothelial progenitors. In the present study, we examined the effects of ascorbate, at levels relevant during intravenous infusion therapy, on angiogenesis using an ex vivo an in vivo assay. METHODS: Two assays were used to evaluate effect of high-doses ascorbic acid on angiogenesis: ex vivo rat aortic ring explant assay in Matrigel matrices and in vivo Matrigel plug assay. In aortic rings, we quantified microvessel growth, branching and vessel regression under different treatment conditions. In murine angiogenesis assay, male C57 mice 6-8 weeks old were treated by high-dose ascorbic acid and the number of microvessels was analyzed by histological method. To characterize the population of cells that formed capillary network and microvessels, the sections were stained by CD34 and CD31 antibodies. RESULTS: Results show that sprouting of endothelial tubules from aortic rings was reduced in a concentration-dependent fashion by ascorbate: while controls roughly tripled sprout densities during the study, ascorbate (1 mg/mL, 5.5 mM) actually reduced sprout density. In vivo, the ability of mice to vascularize subcutaneously implanted Matrigel plug was diminished if the mice were treated with 430 mg/kg vitamin C: numbers of vessels, and vessel densities, in plugs from treated mice were roughly 30% less than those in plugs from untreated mice. CONCLUSIONS: We conclude that the inhibition of angiogenesis by ascorbate suggested in vitro is confirmed in vivo, and that angiogenesis inhibition may be one mechanism by which intravenous ascorbate therapy shows efficacy in animal experiments and clinical case studies.

PMID: 20150992 [PubMed]PMCID: PMC2820478Free PMC Article

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Int J Cancer. 2010 Jan 26. [Epub ahead of print]

Incidence of cancers, ischemic cardiovascular diseases and mortality during 5-year follow-up after stopping antioxidant vitamins and minerals supplements: A postintervention follow-up in the SU.VI.MAX Study.

Hercberg S, Kesse-Guyot E, Druesne-Pecollo N, Touvier M, Favier A, Latino-Martel P, Briançon S, Galan P.

Unité de Recherche en Epidémiologie Nutritionnelle, UMR U557 Inserm; U1125 Inra; Cnam; Paris 13, Centre de Recherche en Nutrition Humaine d’Ile-de-France, F-93017 Bobigny, France.


The Supplementation in Vitamins and Mineral Antioxidants Study was a double-blind, placebo-controlled, randomized trial, in which 12,741 French adults (7,713 women aged 35-60 years and 5,028 men aged 45-60 years) received a combination of ascorbic acid (120 mg), vitamin E (30 mg), beta-carotene (6 mg), selenium (100 mug) and zinc (20 mg), or placebo daily for a median follow-up time of 7.5 years [October 1994 to September 2002]. Antioxidant supplementation decreased total cancer incidence and total mortality in men. Postintervention follow-up assessment of total cancer incidence, ischemic cardiovascular disease incidence and total mortality was carried out for 5 years [September 1, 2002, to September 1, 2007]. No late effect of antioxidant supplementation was revealed 5 years after ending the intervention neither on ischemic cardiovascular disease incidence and mortality in both genders nor on cancer incidence in women. Regarding duration of intervention effects in men, the reduced risk of total cancer incidence and total mortality was no longer evident after the 5-year postintervention follow-up. During the postsupplementation period, the relative risk (RR) for total cancer incidence (n = 126) was 0.98 (95% confidence interval [CI], 0.75-1.27) among antioxidant recipients compared to nonrecipients. For total mortality (n = 90), the RR was 0.98 (95% CI, 0.75-1.26) for men receiving antioxidants compared to nonrecipients. In conclusion, beneficial effects of antioxidant supplementation in men disappeared during postintervention follow-up.

PMID: 20104528 [PubMed – as supplied by publisher]

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Nutr Cancer. 2010;62(2):181-9.

Intakes of vitamin A, C, and E, and beta-carotene are associated with risk of cervical cancer: a case-control study in Korea.

Kim J, Kim MK, Lee JK, Kim JH, Son SK, Song ES, Lee KB, Lee JP, Lee JM, Yun YM.

National Cancer Center, Kyunggido 411-769, Korea.


Cervical cancer is one of the most common gynecological malignancies in Korea, although the incidence has been declining in recent years. This study explored whether antioxidant vitamin intakes influenced the risk of cervical cancer. The association between antioxidant vitamin intakes and cervical cancer risk was calculated for 144 cervical cancer cases and 288 age-matched, hospital-based controls using unconditional logistic regression models. Cases reported statistically lower mean dietary intakes of vitamin A, beta -carotene, and vitamin C than did controls. Total intakes of vitamins A and E, which included both dietary and supplement intake, were also lower in cases. Those patients in the highest quartiles of dietary vitamin A, beta -carotene, and vitamin C intakes had statistically significantly lower cervical cancer risks than those in the lowest quartiles for vitamin A, beta -carotene, and vitamin C: odds ratio (OR) = 0.36 [95% confidence interval (CI) = 0.19-0.69), OR = 0.48 (CI = 0.26-0.88), and OR = 0.36 (CI = 0.18-0.69), respectively. Total intakes of vitamins A, C, and E were strongly inversely associated with cervical cancer risk: OR = 0.35 (CI = 0.19-0.65), OR = 0.35 (CI = 0.19-0.66), and OR = 0.53 (CI = 0.28-0.99), respectively. The findings support a role for increased antioxidant vitamin intake in decreasing the risk of cervical cancer. These associations need to be assessed in large prospective studies with long-term follow-up.

PMID: 20099192 [PubMed – indexed for MEDLINE]

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Rocz Panstw Zakl Hig. 2009;60(3):201-6.

[Contemporary view of plant antioxidants role in prevention of civilization diseases]

[Article in Polish]

Czerwiecki L.

Zakład Analizy Zywności, Instytut Biotechnologii Przemysłu Rolno-Spozywczego, Warszawa.


The role of plant antioxidants as factors of civilization diseases prevention was described. The free-radical theory as a mechanism of action of antioxidants was mentioned. The main substances e.g. polyphenols including flavonoids, ascorbic acid, carotenoids and tocoferols were presented. Resveratrol of wine, as an example of possible health beneficial agent was stressed. On the other handsome doubts of beneficial effects of antioxidants e.g. beta-carotene, as supplement of diet, were mentioned. It is possible, that supplementation with flavonoids might create some health risk. But there was highlighted, that vegetables as a source of natural antioxidants are beneficial for health.

PMID: 20063687 [PubMed – indexed for MEDLINE]

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Cell Stem Cell. 2010 Jan 8;6(1):71-9. Epub 2009 Dec 31.

Vitamin C enhances the generation of mouse and human induced pluripotent stem cells.

Esteban MA, Wang T, Qin B, Yang J, Qin D, Cai J, Li W, Weng Z, Chen J, Ni S, Chen K, Li Y, Liu X, Xu J, Zhang S, Li F, He W, Labuda K, Song Y, Peterbauer A, Wolbank S, Redl H, Zhong M, Cai D, Zeng L, Pei D.

Stem Cell and Cancer Biology Group, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China.


Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by defined factors. However, the low efficiency and slow kinetics of the reprogramming process have hampered progress with this technology. Here we report that a natural compound, vitamin C (Vc), enhances iPSC generation from both mouse and human somatic cells. Vc acts at least in part by alleviating cell senescence, a recently identified roadblock for reprogramming. In addition, Vc accelerates gene expression changes and promotes the transition of pre-iPSC colonies to a fully reprogrammed state. Our results therefore highlight a straightforward method for improving the speed and efficiency of iPSC generation and provide additional insights into the mechanistic basis of the reprogramming process. Copyright 2010 Elsevier Inc. All rights reserved.

PMID: 20036631 [PubMed – indexed for MEDLINE]

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Anticancer Res. 2009 Dec;29(12):5023-31.

Tumor-specific cytotoxicity and type of cell death induced by gefitinib in oral squamous cell carcinoma cell lines.

Chu Q, Amano O, Kanda Y, Kunii S, Wang Q, Sakagami H.

Division of Pharmacology, Meikai University School of Dentistry, Sakado, Saitama, Japan.


Gefitinib is an orally active, selective epidermal growth factor receptor-tyrosine kinase inhibitor. The present study was aimed at evaluating the antitumor activity of gefitinib alone or in combination with other antitumor agents. Gefitinib showed higher cytotoxicity against five human tumor cell lines (HSC-2, HSC-3, HSC-4, T98G and U87MG) than against three human normal oral cells (gingival fibroblast HGF, pulp cell HPC and periodontal ligament fibroblast HPLF). Gefitinib showed little or no growth stimulation effects at lower concentrations (so-called hormetic effect). Non-cytotoxic concentration of gefitinib effectively enhanced the cytotoxicity of docetaxel against HSC-2 and T98G cell, but failed to enhance the cytotoxicity of other antitumor agents (mitoxantrone, doxorubicin, methotrexate, cisplatin, sodium ascorbate, sodium fluoride) or herbal extracts (Drynaria baronii, Angelica sinensis and Cornus officinalis Sieb. et Zucc). Gefitinib alone and combined with docetaxel induced internucleosomal DNA fragmentation and caspase-3 activation in human promyelocytic leukemia HL-60 cells, but not in HSC-2 or T98G cells. Combination treatment with gefitinib and docetaxel induced the formation of acidic organelles (stained with acridine orange) and mitochondrial shrinkage, vacuolization and production of autophagosome and the loss of cell surface microvilli, without destruction of cell surface and nuclear membranes in HSC-2 and T98G cells (demonstrated by transmission electron microscopy), suggesting the induction of autophagy in HSC-2 and T98G cells.

PMID: 20044612 [PubMed – indexed for MEDLINE]

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Anticancer Res. 2009 Nov;29(11):4571-4.

Reduction of oxidative DNA fragmentation by ascorbic acid, zinc and N-acetylcysteine in nasal mucosa tissue cultures.

Baumeister P, Huebner T, Reiter M, Schwenk-Zieger S, Harréus U.

Department of Otolaryngology, University of Munich, Marchioninistr. 15, 81377 Munich, Germany.


Oxidative stress is one major factor in upper aerodigestive tract carcinogenesis. Reactive oxygen species derived from environmental sources, cigarette smoke or cellular metabolism, constantly attack large molecules within the cell. While damaged lipids and proteins can be replaced, oxidative DNA damage needs to be repaired. Damage exceeding DNA repair capacity might lead to permanent mutations. Ascorbic acid, zinc and N-acetylcysteine are widely used as supplementations during upper aerodigestive tract infections. Therefore we chose to investigate their potential in DNA protection. We produced so called “mini-organ” cultures of nasal mucosa, three-dimensional tissue cubes coated with ciliated epithelium, for repeated incubation with ascorbic acid, zinc and N-acetylcysteine at different concentrations. This model has several advantages with respect to repeated incubations, metabolic competence of cells and standardized conditions compared to cell line experiments or animal models. After washing twice, oxidative damage was induced by hydrogen peroxide. Resulting DNA fragmentation was analyzed using the FPG-comet assay, a special modification of the alkaline single-cell microgel electrophoresis for the detection of the most prevalent oxidative DNA base modification. DNA damage was reduced within a range of 45-60%. Cell viability after incubations with hydrogenperoxide was >90%. Our results show strong DNA protective effects of the substances tested in accordance with epidemiological studies linking a diet rich in antioxidative micronutrients with a lowered risk for cancer development. The reasons for the failure of large antioxidant supplementation interventional trials need to be further investigated.

PMID: 20032405 [PubMed – indexed for MEDLINE]

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BMC Cancer. 2009 Dec 21;9:458.

Pre-radiotherapy plasma carotenoids and markers of oxidative stress are associated with survival in head and neck squamous cell carcinoma patients: a prospective study.

Sakhi AK, Russnes KM, Thoresen M, Bastani NE, Karlsen A, Smeland S, Blomhoff R.

Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 0316 Oslo, Norway.


BACKGROUND: The purpose of this study was to compare plasma levels of antioxidants and oxidative stress biomarkers in head and neck squamous cell carcinoma (HNSCC) patients with healthy controls. Furthermore, the effect of radiotherapy on these biomarkers and their association with survival in HNSCC patients were investigated. METHODS: Seventy-eight HNSCC patients and 100 healthy controls were included in this study. Follow-up samples at the end of radiotherapy were obtained in 60 patients. Fifteen antioxidant biomarkers (6 carotenoids, 4 tocopherols, ascorbic acid, total antioxidant capacity, glutathione redox potential, total glutathione and total cysteine) and four oxidative stress biomarkers (total hydroperoxides, gamma-glutamyl transpeptidase, 8-isoprostagladin F2alpha and ratio of oxidized/total ascorbic acid) were measured in plasma samples. Analysis of Covariance was used to compare biomarkers between patients and healthy controls. Kaplan-Meier plots and Cox’ proportional hazards models were used to study survival among patients. RESULTS: Dietary antioxidants (carotenoids, tocopherols and ascorbic acid), ferric reducing antioxidant power (FRAP) and modified FRAP were lower in HNSCC patients compared to controls and dietary antioxidants decreased during radiotherapy. Total hydroperoxides (d-ROMs), a marker for oxidative stress, were higher in HNSCC patients compared to controls and increased during radiotherapy. Among the biomarkers analyzed, high levels of plasma carotenoids before radiotherapy are associated with a prolonged progression-free survival (hazard rate ratio: 0.42, 95% CI: 0.20-0.91, p = 0.03). Additionally, high relative increase in plasma levels of d-ROMs (hazard rate ratio: 0.31, 95% CI: 0.13-0.76, p = 0.01) and high relative decrease in FRAP (hazard rate ratio: 0.42, 95% CI: 0.17-0.998, p = 0.05) during radiotherapy are also positively associated with survival. CONCLUSIONS: Biomarkers of antioxidants and oxidative stress are unfavourable in HNSCC patients compared to healthy controls, and radiotherapy affects many of these biomarkers. Increasing levels of antioxidant biomarkers before radiotherapy and increasing oxidative stress during radiotherapy may improve survival indicating that different factors/mechanisms may be important for survival before and during radiotherapy in HNSCC patients. Thus, the therapeutic potential of optimizing antioxidant status and oxidative stress should be explored further in these patients.

PMID: 20025747 [PubMed – indexed for MEDLINE]PMCID: PMC2813240Free PMC Article

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Exp Oncol. 2009 Dec;31(4):214-9.

Antiangiogenic properties of a nutrient mixture in a model of hemangioma.

Roomi MW, Kalinovsky T, Niedzwiecki A, Rath M.

Dr. Rath Research Institute, Oncology Division, Santa Clara, CA 95050, USA.


The pathogenesis of hemangiomas is still largely unknown and the current therapy, such as systemic corticosteroid, vincristine, and interferon-alpha, is toxic and remains unsatisfactory. A nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract has shown significant anti-angiogenic and anti-tumor effect against a number of cancer cell lines. Aim: Using a mouse hemangioendothelioma model, we investigated the efficacy of NM. We also tested the effect of NM in vitro, evaluating cell viability, MMP secretion, invasion, morphology and apoptosis. METHODS: Athymic nude mice, 5-6 weeks old, were inoculated with 3 x10(6) EOMA cells subcutaneously and randomly divided into two groups; group A was fed a regular diet and group B – a regular diet supplemented with 0.5% NM. Four weeks later, the mice were sacrificed and their tumors were excised, weighed and processed for histology. We also tested the effect of NM in vitro. RESULTS: NM inhibited the growth of tumors by 50%. In vitro, NM exhibited dose response cytotoxicity with 10%, 30% and 55% at 10, 100 and 1000 microg/ml. Invasion through Matrigel was inhibited at 50, 100 and 500 microg/ml by 25%, 30% and 100% respectively. NM induced dose-dependent apoptosis of EOMA cells. CONCLUSIONS: These results suggest that NM may have therapeutic potential in treating infantile hemangioendotheliomas and, perhaps, other cutaneous vascular tumors.

PMID: 20010532 [PubMed – indexed for MEDLINE]

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Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G267-74. Epub 2009 Nov 19.

Molecular determinants dictating cell surface expression of the human sodium-dependent vitamin C transporter-2 in human liver cells.

Subramanian VS, Marchant JS, Said HM.

Department of Medicine, University of California, Irvine, CA, USA.


The human sodium-dependent vitamin C transporter-2 (hSVCT2) plays an important role in cellular accumulation of ascorbic acid in liver cells. However, little is known about the molecular determinants that direct hSVCT2 to the cell surface in hepatocytes. We addressed this issue using live cell imaging methods to resolve the distribution and trafficking of truncated or mutated hSVCT2 constructs in a cellular model of human hepatocytes, HepG2 cells. Whereas a full-length hSVCT2-yellow fluorescent protein (YFP) fusion protein was functionally expressed at the cell surface in HepG2 cells, serial truncation and mutation analysis demonstrated an essential role for both NH(2)- and COOH-terminal sequence(s) for cell surface expression and function. Video-rate confocal imaging showed evidence of dynamic hSVCT2-YFP containing intracellular trafficking vesicles, the motility of which was impaired following disruption of microtubules using nocodazole. However, in a HepG2 cell line stably expressing hSVCT2-YFP at the cell surface, plasma membrane levels of hSVCT2 were unaffected by inhibition of microtubule-associated motor proteins; rather, surface expression of hSVCT2-YFP was increased following treatment with myosin inhibitors. Together, these results show that 1) both NH(2)- and COOH-terminal sequences are essential for proper localization of hSVCT2, 2) cell surface delivery is dependent on intact microtubules, and 3) peripheral microfilaments regulate insertion and retrieval of hSVCT2 into the plasma membrane.

PMID: 19926816 [PubMed – indexed for MEDLINE]PMCID: PMC2822508 [Available on 2011/2/1]

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