Letter to the Editor: Heaney ML et al. Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs. Cancer Res 2008; 68:19:8031-8038

We read with great interest the paper by Heaney ML, et al (1), which demonstrates that dehydroascorbic acid (DHA), the oxidized form of Vitamin C, negatively impacts chemotherapeutic efficacy in leukemia and lymphoma cell lines and in a murine tumour model. In contrast, there is a larger body of evidence that has found that the reduced form of Vitamin C, ascorbic acid (AA) augments chemotherapy efficacy, reverses chemotherapy resistance in chemotherapy resistant cell lines, and increases drug accumulation in numerous in vitro and in vivo models (2-24). Moreover, the combination of AA with cisplatin in murine Dalton's lymphoma was found not only to increase chemotherapeutic efficacy but also to increase survival as well (22-23) and the same has also been shown with AA in combination with cyclophosphamide (24). The volume of research that supports the use of AA in combination with chemotherapy is even greater if the research of the use of AA in combination with Arsenic trioxide is included (35). There are also two human randomized trials comparing chemotherapy with and without AA. These clinical trials did not show signs of interference (25, 26).

While some cell lines appear to be more sensitive to AA chemotherapy combinations than others, there are likely other factors that explain the difference between the positive impact of the use of AA in combination with chemotherapeutic agents listed above and the negative impact of the use of DHA in combination with chemotherapy found by Heaney et al. There are important interplays between AA & DHA to consider, which may explain this paradox. Unlike DHA, AA is an electron donor, which is important in signal transduction pathways (27). Flooding both the extracellular and intracellular pool with DHA may disrupt important homeostasis, which includes AA's ability to induce cell death through the release of apoptosis-inducing factor from the cancer cell mitochondria (28). In fact, research by Koh WS et al., demonstrates that AA's ability to inhibit leukemic cell growth is dependent on its concentration in culture medium rather than in its intracellular concentration (29). No AA was found in the culture supernatant treated with DHA. Interestingly, in this study, the growth of leukemic cells was dose-dependently inhibited by AA but not by DHA. As Heaney,et al. had mentioned, AA is the principle form of Vitamin C in the serum, which may also hold some significance and potential chemo-modulatory impact on cell membranes and also on cell mediated immunity. In other words, treatment with DHA may negatively impact chemotherapeutic response even though the reverse may be true with AA treatment.

Patients with cancer have lower serum AA levels even when intakes are greater than controls (30, 31). Data also suggests that cancer patients have serum and CSF ascorbyl radical formation (i.e. free radical stress). The oxidized form of Vitamin C (i.e. DHA) may be an added stress, especially during chemotherapy (32), consistent with the findings of Heaney et al. In humans, AA in combination with chemotherapeutic agents have not shown adverse effects in randomized trials and in clinical reports (25-26, 33-35). As the general public consumes AA (for which the weight of the evidence suggests a positive impact on chemotherapy in cell-line and murine tumour models) rather than DHA, more research should be done with AA in combination with chemotherapy in animal models to better understand the current findings and their implications with respect to Vitamin C use during chemotherapy.

References

1. Heaney ML et al. Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs. Cancer Res 2008; 68:19:8031-8038
2. Prasad KN et al. Modification of the effect of tamoxifen, Cisplatinum, DTIC, and interferon-alpha 2b on human melanoma cells in culture by a mixture of vitamins. Nutr Cancer 1994; 22:3:233-45
3. Chiang CD et al. Ascorbic acid increases drug accumulation and reverses Vincristine resistance of human non-small-cell lung cancer. Biochem J 1994; 301 (Pt 3): 759-64
4. Song EJ et al. Potentiation of growth inhibition due to Vincristine by ascorbic acid in a resistant human non-small cell lung cancer cell line. Eur J Pharmacol 1995; 292:2:119-25
5. Kurbacher CM et al. Ascorbic acid (Vitamin C) improves the antineoplastic activity of doxorubicin, Cisplatinum, and pacltitaxel in human breast carcinoma cells in vitro. Cancer Letter 1996; 103:2:183-9
6. Wells WW et al. Ascorbic acid and cell survival of Adriamycin resistant and sensitive MCF-7 breast tumor cells. Free Radic Biol Med 1995; 18:4:699-708
7. Marian M et al. Potentiation of the biological activities of daunomycin and Adriamycin by ascorbic acid and dimethylsulfoxide. Experientia 1982. 38:5:573-4
8. Nagy B et al. Chemosensitizing effect of Vitamin C in combination with 5-fluorouracil in vitro. In Vivo 2003; 17:3:289-92
9. Kammerer C et al. Enhancement of mitomycin C efficiency by Vitamin C, E-acetate and beta-carotene under irradiation. A study in vitro. Anticancer Res 1999; 19:6B:5319-21
10. Abdel-Latiff MM et al. Vitamin C enhances chemosensitization of esophageal cancer cells in vitro. J Chemother 2005; 17:5:539-49
11. Catani MV et al. Ascorbate up-regulates MLH1 (Mut L homologue-1) and p73: implications for the cellular response to DNA damage. Biochem J 2002; 364 (Pt 2): 441-7
12. Reddy VG et al. Vitamin C augments chemotherapeutic response of cervical carcinoma HeLa cells by stabilizing p53. Biochem Biophys Res Commun 2001; 282:2:409-15
13. Tarumoto T et al. Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line. Exp Hematol 2004; 32:4:375-81
14. Yam D et al. Suppression of tumor growth and metastasis by dietary fish oil combined with vitamins E and C and cisplatin. Cancer Chemother Pharmacol 2001; 47:1:34-40
15. Kassouf W et al. Vitamins C and K3 sensitize human urothelial tumors to Gemcitabine. J Urol 2006. 176 (4 Pt 1): 1642-7
16. Taper HS et al. Non-toxic sensitization of cancer chemotherapy by combined Vitamin C and K3 pretreatment in a mouse tumor resistant to oncovin. Anticancer Res. 1992; 5:1651-4.
17. Pathak AK et al. Potentiation of the effect of paclitaxel and carboplatin by antioxidant mixture on human lung cancer h520 cells. J Am Coll Nutr. 2002 Oct;21:5:416-21.
18. Shimpo K et al. Ascorbic acid and adriamycin toxicity. Am J Clin Nutr. 1991;54:6 Suppl:1298S-1301S.
19. Woz'niak G et al. Influence of vitamins C and E on cytotoxic activity of adriamycin in chosen cell cultures. Acta Pol Pharm. 2002;59:1:31-5.
20. Casciari JJ et al. Cytotoxicity of ascorbate, lipoic acid, and other antioxidants in hollow fibre in vitro tumours. Br J Cancer. 2001; 84:11:1544-50.
21. De Loecker W et al. Effects of sodium ascorbate (Vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) treatment on human tumor cell growth in vitro. II. Synergism with combined chemotherapy action. Anticancer Res. 1993;13:1:103-6.
22. Sarna S et al. Chemo-immunotherapeutical studies on Dalton's lymphoma mice using cisplatin and ascorbic acid: synergistic antitumor effect in vivo and in vitro. Arch Immunol Ther Exp (Warsz) 1993; 41:5-6:327-33
23. Prasad SB et al. Use of subtherapeutical dose of cisplatin and Vitamin C against murine Dalton's lymphoma. Pol J Pharmacol Pharm 1992; 44:4:383-91
24. Nichold BM et al. The effects of cyclophosphamide alone and in combination with ascorbic acid against murine ascites Dalton's lymphoma. Indian J Pharmacol 2006; 38:4:260-265
25. Pathak AK et al. Chemotherapy alone vs. chemotherapy plus high dose multiple antioxidants in patients with advanced non small cell lung cancer. J Am Coll Nutr 2005; 24:1:16-21
26. Weijl NI et al. Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study. Eur J Cancer 2004;40:10:1713-23.
27. Carcamo JM et al. Vitamin C is a kinase inhibitor: dehydroascorbic acid inhibits IkappaBalpha kinase beta. Mol Cell Bio 2004; 24:15:6645-52
28. Seung-Woo Hong et al. Ascorbate (Vitamin C) induces cell death through the apoptosis-inducing factor in human breast cancer cells. Oncology Rep 2007; 18:811-15
29. Koh WS et al. Differential effects and transport kinetics of ascorbate derivatives in leukemic cell lines. Anticancer Res 1998; 18:4A:2487-93
30. Nevestani TR et al. Vitamin C status in Iranian children with acute lymphoblastic leukemia: evidence of increased utilization. J Pediatr Gastroenterol Nutr 2007; 45:1:141-4
31. Anthony HM et al. Severe hypovitaminosis in lung-cancer patients: the utilization of Vitamin C in surgical repair and lymphocyte-related host resistance. Br J Cancer 1982; 46:3:354-67
32. Nakagawa K et al. Effect of chemotherapy on ascorbate and ascorbyl radical in the cerebrospinal fluid and serum of acute lymphpblastic leukemia. Cell Mol Biol 2000; 46:8:13781
33. Drisko JA et al. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr 2003; 22:2:118-23
34. Riordan NH et al. Intravenous Vitamin C as a chemotherapeutic agent: a report on clinical cases. PRHSJ 2004; 23:2:115-18
35. Chang J et al. Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: a Wisconsin Oncology Network study. Hematol Oncol 2008; Jul 31.