In Vitro Studies
Numerous studies have demonstrated that pharmacological doses of ascorbic acid (0.1–100 mM) decrease cell proliferation in a variety of cancer cell lines.[1-5] Specifically, decreases in cell proliferation after ascorbic acid treatment have been reported for prostate, pancreatic,[7,8] hepatocellular, colon, mesothelioma, and neuroblastoma  cell lines.
The potential mechanisms through which treatment with high-dose ascorbic acid may exert its effects on cancer cells have been extensively investigated. Several studies have demonstrated that the in vitro direct cytotoxic effect of ascorbic acid on various types of cancer cells is mediated through a chemical reaction that generates hydrogen peroxide.[1,7] Reviewed in [13,14] Treating colon cancer cells with 2 mM to 3 mM of ascorbic acid resulted in downregulation of specificity protein (Sp) transcription factors and Sp-regulated genes involved in cancer progression. One study suggested that ascorbate-mediated prostate cancer cell death may occur through activation of an autophagy pathway.
Research has suggested that pharmacological doses of ascorbic acid enhance the effects of arsenic trioxide on ovarian cancer cells, gemcitabine on pancreatic cancer cells, and combination treatment of gemcitabine and epigallocatechin-3-gallate (EGCG) on mesothelioma cells.
Findings from one study reported in 2012 suggested that high-dose ascorbate increases radiosensitivity of glioblastoma multiforme cells, resulting in more cell death than from radiation therapy alone.
However, not all studies combining vitamin C with chemotherapy have shown improved outcomes. Treating leukemia and lymphoma cells with dehydroascorbic acid (the oxidized form of vitamin C that increases levels of intracellular ascorbic acid) reduced the cytotoxic effects of various antineoplastic agents tested, including doxorubicin, methotrexate, and cisplatin (relative reductions in cytotoxicity ranged from 30% to 70%). In another study, multiple myeloma cells were treated with bortezomib and/or plasma obtained from healthy volunteers who had taken vitamin C supplements. Cells treated with a combination of bortezomib and volunteers’ plasma exhibited lower cytotoxicity than did cells treated with bortezomib alone.
Studies have demonstrated tumor growth inhibition after treatment with pharmacological ascorbate in animal models of pancreatic cancer,[1,7,8] liver cancer, prostate cancer, sarcoma, mesothelioma, and ovarian cancer.
The effects of high-dose ascorbic acid in combination with standard treatments on tumors have been investigated. In a mouse model of pancreatic cancer, the combination of gemcitabine (30 or 60 mg /kg every 4 days) and ascorbate (4 g /kg daily) resulted in greater decreases in tumor volume and weight, compared with gemcitabine treatment alone. According to a study reported in 2012, ascorbate enhanced the cancer cell–killing effects of photodynamic therapy in mice injected with breast cancer cells. A study of mouse models of ovarian cancer found that ascorbate enhanced the tumor inhibitory effect of carboplatin and paclitaxel, first-line chemotherapy used in ovarian cancer.
Using N-acetylcysteine (NAC) and vitamin C, researchers showed in 2007 that these compounds, both thought to act predominantly as antioxidants, may have antitumorigenic actions in vivo by decreasing levels of hypoxia -inducible factor (HIF)-1, a transcription factor that targets vascular endothelial growth factor (VEGF) and plays a role in angiogenesis.
There have also been reports of animal studies in which vitamin C has interfered with the anticancer activity of various drugs. In a study reported in 2008, administration of dehydroascorbic acid to lymphoma-xenograft mice prior to doxorubicin treatment resulted in significantly larger tumors than did treatment with doxorubicin alone. Notably, this study used dehydroascorbate, the oxidized form of vitamin C that is known to be transported actively into cells and then reduced to vitamin C. Treating multiple myeloma xenograft mice with a combination of oral vitamin C and bortezomib resulted in significantly greater tumor volume than did treatment with bortezomib alone. This increase in tumor volume was caused by a chemical reaction that occurs in the gastrointestinal tract but does not appear to be relevant to intravenous administration.
- Chen P, Stone J, Sullivan G, et al.: Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. Free Radic Biol Med 51 (3): 681-7, 2011. [PUBMED Abstract]
- Chen Q, Espey MG, Krishna MC, et al.: Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A 102 (38): 13604-9, 2005. [PUBMED Abstract]
- Verrax J, Calderon PB: Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med 47 (1): 32-40, 2009. [PUBMED Abstract]
- Chen Q, Espey MG, Sun AY, et al.: Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc Natl Acad Sci U S A 105 (32): 11105-9, 2008. [PUBMED Abstract]
- Frömberg A, Gutsch D, Schulze D, et al.: Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs. Cancer Chemother Pharmacol 67 (5): 1157-66, 2011. [PUBMED Abstract]
- Chen P, Yu J, Chalmers B, et al.: Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy. Anticancer Drugs 23 (4): 437-44, 2012. [PUBMED Abstract]
- Du J, Martin SM, Levine M, et al.: Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res 16 (2): 509-20, 2010. [PUBMED Abstract]
- Espey MG, Chen P, Chalmers B, et al.: Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med 50 (11): 1610-9, 2011. [PUBMED Abstract]
- Lin ZY, Chuang WL: Pharmacologic concentrations of ascorbic acid cause diverse influence on differential expressions of angiogenic chemokine genes in different hepatocellular carcinoma cell lines. Biomed Pharmacother 64 (5): 348-51, 2010. [PUBMED Abstract]
- Pathi SS, Lei P, Sreevalsan S, et al.: Pharmacologic doses of ascorbic acid repress specificity protein (Sp) transcription factors and Sp-regulated genes in colon cancer cells. Nutr Cancer 63 (7): 1133-42, 2011. [PUBMED Abstract]
- Takemura Y, Satoh M, Satoh K, et al.: High dose of ascorbic acid induces cell death in mesothelioma cells. Biochem Biophys Res Commun 394 (2): 249-53, 2010. [PUBMED Abstract]
- Hardaway CM, Badisa RB, Soliman KF: Effect of ascorbic acid and hydrogen peroxide on mouse neuroblastoma cells. Mol Med Report 5 (6): 1449-52, 2012. [PUBMED Abstract]
- Du J, Cullen JJ, Buettner GR: Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta 1826 (2): 443-57, 2012. [PUBMED Abstract]
- Levine M, Padayatty SJ, Espey MG: Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr 2 (2): 78-88, 2011. [PUBMED Abstract]
- Hong SW, Lee SH, Moon JH, et al.: SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment. Oncogene 32 (12): 1508-17, 2013. [PUBMED Abstract]
- Ong PS, Chan SY, Ho PC: Differential augmentative effects of buthionine sulfoximine and ascorbic acid in As2O3-induced ovarian cancer cell death: oxidative stress-independent and -dependent cytotoxic potentiation. Int J Oncol 38 (6): 1731-9, 2011. [PUBMED Abstract]
- Martinotti S, Ranzato E, Burlando B: In vitro screening of synergistic ascorbate-drug combinations for the treatment of malignant mesothelioma. Toxicol In Vitro 25 (8): 1568-74, 2011. [PUBMED Abstract]
- Herst PM, Broadley KW, Harper JL, et al.: Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radic Biol Med 52 (8): 1486-93, 2012. [PUBMED Abstract]
- Heaney ML, Gardner JR, Karasavvas N, et al.: Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res 68 (19): 8031-8, 2008. [PUBMED Abstract]
- Perrone G, Hideshima T, Ikeda H, et al.: Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia 23 (9): 1679-86, 2009. [PUBMED Abstract]
- Pollard HB, Levine MA, Eidelman O, et al.: Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In Vivo 24 (3): 249-55, 2010 May-Jun. [PUBMED Abstract]
- Yeom CH, Lee G, Park JH, et al.: High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis. J Transl Med 7: 70, 2009. [PUBMED Abstract]
- Wei Y, Song J, Chen Q, et al.: Enhancement of photodynamic antitumor effect with pro-oxidant ascorbate. Lasers Surg Med 44 (1): 69-75, 2012. [PUBMED Abstract]
- Ma Y, Chapman J, Levine M, et al.: High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med 6 (222): 222ra18, 2014. [PUBMED Abstract]
- Gao P, Zhang H, Dinavahi R, et al.: HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12 (3): 230-8, 2007. [PUBMED Abstract]