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      Enhanced Anticancer Effect of Adding Magnesium to Vitamin C Therapy: Inhibition of Hormetic Response by SVCT-2 Activation

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          Abstract

          l-Ascorbic acid (vitamin C, AA) is known as an antioxidant, but at high concentrations, AA can kill cancer cells through a prooxidant property. Sodium-dependent vitamin C transporter family-2 (SVCT-2) determines the cellular uptake of AA, and the activity of SVCT-2 is directly related to the anticancer activity of AA. Cancer cells that showed high SVCT-2 expression levels were more sensitive to AA treatment than cancer cells with low SVCT-2 expression levels. Cells with low SVCT-2 expression showed a hormetic response to a low dose of AA. Magnesium ions, which are known to activate SVCT-2, could increase the V max value of SVCT-2, so we investigated whether providing magnesium supplements to cancer cells with low SVCT-2 expression that had shown a hormetic response to AA would elevate the V max value of SVCT-2, allowing more AA to accumulate. To evaluate the effects of magnesium on cancer cells, MgSO 4 and MgCl 2 were screened as magnesium supplements; both forms showed synergistic anticancer effects with AA. Taken together, the results of this study suggest that magnesium supplementation enhanced the anticancer effect of AA by inhibiting the hormetic response at a low dose. This study has also demonstrated that AA treatment with magnesium supplementation provided more effective anticancer therapy than AA treatment alone.

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          High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison.

          Ryan Ames, C MOERTEL, Jeffrey O’Connell … (1985)
          It has been claimed that high-dose vitamin C is beneficial in the treatment of patients with advanced cancer, especially patients who have had no prior chemotherapy. In a double-blind study 100 patients with advanced colorectal cancer were randomly assigned to treatment with either high-dose vitamin C (10 g daily) or placebo. Overall, these patients were in very good general condition, with minimal symptoms. None had received any previous treatment with cytotoxic drugs. Vitamin C therapy showed no advantage over placebo therapy with regard to either the interval between the beginning of treatment and disease progression or patient survival. Among patients with measurable disease, none had objective improvement. On the basis of this and our previous randomized study, it can be concluded that high-dose vitamin C therapy is not effective against advanced malignant disease regardless of whether the patient has had any prior chemotherapy.
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            Phase I Evaluation of Intravenous Ascorbic Acid in Combination with Gemcitabine and Erlotinib in Patients with Metastatic Pancreatic Cancer

            Daniel Monti, Edith Mitchell, Anthony J. Bazzan … (2012)
            Background Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy. Methods and Findings 14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease. Conclusions These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration. Trial Registration Clinicaltrials.gov NCT00954525
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              Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer.

              Craig Cameron, L PAULING (1978)
              A study has been made of the survival times of 100 terminal cancer patients who were given supplemental ascorbate, usually 10 g/day, as part of their routine management and 1000 matched controls, similar patients who had received the same treatment except for the ascorbate. The two sets of patients were in part the same as those used in our earlier study [Cameron, E. & Pauling, L. (1976) Proc. Natl. Acad. Sci. USA 73, 3685-3689]. Tests confirm that the ascorbate-treated patients and the matched controls are representative subpopulations of the same population of "untreatable" patients. Survival times were measured not only from the date of "untreatability" but also from the precisely known date of first hospital attendance for the cancer that eventually reached the terminal stage. The ascorbate-treated patients were found to have a mean survival time about 300 days greater than that of the controls. Survival times greater than 1 yr after the date of untreatability were observed for 22% of the ascorbate-treated patients and for 0.4% of the controls. The mean survival time of these 22 ascorbate-treated patients is 2.4 yr after reaching the apparently terminal stage; 8 of the ascorbate-treated patients are still alive, with a mean survival time after untreatability of 3.5 yr.
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                Author and article information

                Contributors
                Sukchan Lee
                Chang-Hwan Yeom
                Journal
                Journal ID (nlm-ta): Transl Oncol
                Journal ID (iso-abbrev): Transl Oncol
                Title: Translational Oncology
                Publisher: Neoplasia Press
                ISSN (Electronic): 1936-5233
                Publication date PMC-release: 31 December 2019
                Publication date Collection: February 2020
                Publication date (Electronic): 31 December 2019
                Volume: 13
                Issue: 2
                Pages: 401-409
                Affiliations
                [∗ ]College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea
                [† ]Yeom Chang-Hwan Hospital, Seoul, 06605, Republic of Korea
                [‡ ]Department of Applied Chemistry, Dongduk Women's University, Seoul, 02748, Republic of Korea
                [§ ]Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, Republic of Korea
                Author notes
                [∗ ]Address all correspondence to: Sukchan Lee cell4u@ 123456skku.edu
                [∗∗ ]Chang-Hwan Yeom lymphych@ 123456hanmail.net
                Article
                Publisher ID: S1936-5233(19)30254-2
                DOI: 10.1016/j.tranon.2019.10.017
                PMC ID: 6940627
                PubMed ID: 31901552
                SO-VID: 575c8d62-d981-4339-bb5c-b9b3c41d1980
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 3 May 2019
                Date revision received : 24 October 2019
                Date accepted : 29 October 2019
                Categories
                Subject: Original article

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