Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?

Ichim, Thomas E.; Minev, Boris; Braciak, Todd A.; Luna, Brandon; Hunninghake, Ronald; Mikirova, Nina; Jackson, James; González, Michael J.; Miranda-Massari, Jorge R.; Alexandrescu, Doru T; Dasanu, Constantin A; Bogin, Vladimir; Ancans, Janis; Stevens, R. Brian; Markosian, Boris; Koropatnick, James; Chen, Chien-Shing; Riordan, Neil H

doi:10.1186/1479-5876-9-25

Cited by 23 publications

(20 citation statements)

References 217 publications

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“…Scurvy, which results from severe dietary lack of ascorbate, exhibits generalized stromal changes identical to local stromal changes observed in cancer in the immediate vicinity of invading neoplastic cells (38). Thus, ascorbate supplementation to cancer patients has been proposed to reverse their scorbutic symptoms and treat the cancer (13,39). The results of this study support this proposal.…”

Section: Discussionmentioning

confidence: 99%

Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice

Cha

Roomi

Ivanov

et al. 2012

International Journal of Oncology

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Degradation of the extracellular matrix (ECM) plays a critical role in the formation of tumors and metastasis and has been found to correlate with the aggressiveness of tumor growth and invasiveness of cancer. Ascorbic acid, which is known to be essential for the structural integrity of the intercellular matrix, is not produced by humans and must be obtained from the diet. Cancer patients have been shown to have very low reserves of ascorbic acid. Our main objective was to determine the effect of ascorbate supplementation on metastasis, tumor growth and tumor immunohistochemistry in mice unable to synthesize ascorbic acid [gulonolactone oxidase (gulo) knockout (KO)] when challenged with B16FO melanoma or 4T1 breast cancer cells. Gulo KO female mice 36-38 weeks of age were deprived of or maintained on ascorbate in food and water for 4 weeks prior to and 2 weeks post intraperitoneal (IP) injection of 5×105 B16FO murine melanoma cells or to injection of 5×105 4T1 breast cancer cells into the mammary pad of mice. Ascorbate-supplemented gulo KO mice injected with B16FO melanoma cells demonstrated significant reduction (by 71%, p=0.005) in tumor metastasis compared to gulo KO mice on the control diet. The mean tumor weight in ascorbate supplemented mice injected with 4T1 cells was reduced by 28% compared to tumor weight in scorbutic mice. Scorbutic tumors demonstrated large dark cores, associated with increased necrotic areas and breaches to the tumor surface, apoptosis and matrix metalloproteinase-9 (MMP-9), and weak, disorganized or missing collagen I tumor capsule. In contrast, the ascorbate-supplemented group tumors had smaller fainter colored cores and confined areas of necrosis/apoptosis with no breaches from the core to the outside of the tumor and a robust collagen I tumor capsule. In both studies, ascorbate supplementation of gulo KO mice resulted in profoundly decreased serum inflammatory cytokine interleukin (IL)-6 (99% decrease, p=0.01 in the B16F0 study and 85% decrease, p=0.08 in the 4T1 study) compared to the levels in gulo KO mice deprived of ascorbate. In the B16FO study, ascorbate supplementation of gulo KO mice resulted in profoundly decreased serum VEGF (98% decrease, p=0.019 than in the scorbutic gulo KO mice). As expected, mean serum ascorbate level in ascorbate-restricted mice was 2% (p<0.001) of the mean ascorbate levels in supplemented mice. In conclusion, ascorbate supplementation hinders metastasis, tumor growth and inflammatory cytokine secretion as well as enhanced encapsulation of tumors elicited by melanoma and breast cancer cell challenge in gulo KO mice.

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Section: Discussionmentioning

confidence: 99%

Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice

Cha

Roomi

Ivanov

et al. 2012

International Journal of Oncology

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“…Ascorbate plays a role in limiting inflammation, regulating cytokine production, and boosting the immune system [2][3][4][5][6][7][8]. It has a variety of properties that have generated interest in using it against cancer [9][10][11][12][13]: it enhances natural killer cell activity [14,15], increases collagen synthesis [16], inhibits capillary tubule formation (angiogenesis) [17,18], reduces inflammation in cancer patients [3], at millimolar concentrations, shows cytotoxicity against cancer cells [19][20][21][22][23][24] and the ability to reduce tumor growth in vivo [25][26][27][28][29][30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Gene expression response to ascorbic acid in mice implanted with sarcoma S180 cells

Mikirova¹,

Scimeca²

2016

J Transl Sci

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In recent years, increasing numbers of studies demonstrated that high-dose ascorbate, which can be achieved by intravenous infusion, has cytotoxic effects on cancer cells in vitro and in vivo. There are many hypotheses of anti-cancer mechanisms of high dose ascorbate including a pro-oxidative mechanism, inhibition of angiogenesis and inflammation, enhancement of the anticancer effect of chemotherapy and reduction of chemotherapy-induced side effects. In addition, in recent years there were studies showing that ascorbic acid has effect on gene expression and epigenetic phenomena. In our study we analyzed, by using animal model, the effect of pharmacological concentrations of ascorbic acid on several gene expressions involved in tumorigenesis. To test the effects of ascorbic acid on gene expression, we treated mice with two different concentrations of ascorbic acid after intraperitoneal administration with sarcoma S-180 cells. The injected doses of ascorbic acid were equivalent to 15 g per 70 kg human and 50 g per 70 kg human. Tissue from tumors, liver and kidney was obtained from mice at the end of three weeks of treatment. The gene expression analysis was computed by real time PCR. The results showed significant difference in expression of gene p53 (p<0.02) in tumor tissue between treated and non-treated groups, and reduction of p53 gene expression by size and spreading of tumors. Ascorbate therapy significantly increased expression of NRF2. The experimental data showed that the maximum ascorbate dosage reduced expression of the tumor promoting gene HIF. The dependence of gene expression on the size of tumors was found for P53, HIF and NF-kB. In summary, the results of our study demonstrated that ascorbate therapy had a significant effect on the expression of several genes relevant to the development or inhibition of cancer. Reduced expression of tumor promoting genes as HIF and increased expression of tumor suppression genes such as p53 support the hypothesis that ascorbic acid can act as a potential agent for the suppression of tumor development.

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“…However, the literature shows controversy over the treatment of cancer including ascorbic acid. Researchers report that in vitro studies of neuroblastoma, bladder cancer, pancreatic cancer, and other tumor types showed cytotoxic effect of ascorbic acid, while in vivo studies supported this anti-cancer potential of the vitamin C. 18 Table 2 shows the clinical and non-clinical studies on the use of ascorbic acid as an antitumor agent in the treatment and/or prevention of cancer, describing its use in several types of cancer or cell lines at different doses/ concentrations and mechanisms of action. Of these, only one clinical study showed patients with metastatic pancreatic cancer treated with ascorbic acid at 0.28; 0.…”

Section: Resultsmentioning

confidence: 99%

Ascorbic acid in the prevention and treatment of cancer

Mata

Carvalho

Alencar

et al. 2016

Rev. Assoc. Med. Bras.

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Mata aMOF da et al. 680rev assoC med bras 2016; 62(7):680-686 This review is aimed at the systematic mapping of ascorbic acid in the prevention and/or treatment of cancer in clinical and non-clinical studies from 2011 to 2015, in order to understand dose-response variations as well as its mechanisms of action as an antioxidant and antitumor agent. Seventy-eight articles were retrieved from the PubMed/Bireme database, of which only 30 included ascorbic acid in the prevention and/or treatment of cancer. However, there are controversies regarding doses and a lack of clinical studies featuring its mechanism of action more clearly. Other studies are needed to understand dose-response variations, as well as its targeting mechanisms of action, both as an antioxidant and antitumor agent, to assist treatment and prevention of cancer, aiming at better quality of life for both patients and the general population.

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Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?

Cited by 23 publications

References 217 publications

Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice

Ascorbate supplementation inhibits growth and metastasis of B16FO melanoma and 4T1 breast cancer cells in vitamin C-deficient mice

Gene expression response to ascorbic acid in mice implanted with sarcoma S180 cells

Ascorbic acid in the prevention and treatment of cancer

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