nach oben

11.09.2024 | REVIEW ARTICLE

High-dose vitamin C as a metabolic treatment of cancer: a new dimension in the era of adjuvant and intensive therapy

verfasst von: Xin Wang, Jia He, Minmin Sun, Shiwan Wang, Jinxiu Qu, Hanping Shi, Benqiang Rao

Erschienen in: Clinical and Translational Oncology

Einloggen, um Zugang zu erhalten

Abstract

The anti-cancer mechanism of High-dose Vitamin C (HDVC) is mainly to participate in the Fenton reaction, hydroxylation reaction, and epigenetic modification, which leads to the energy crisis, metabolic collapse, and severe peroxidation stress that results in the proliferation inhibition or death of cancer cells. However, the mainstream view is that HDVC does not significantly improve cancer treatment outcomes. In clinical work and scientific research, we found that some drugs or therapies can significantly improve the anti-cancer effects of HDVC, such as PD-1 inhibitors that can increase the anti-cancer effects of cancerous HDVC by nearly three times. Here, the adjuvant and intensive therapy and synergistic mechanisms including HDVC combined application of chemoradiotherapies multi-vitamins, targeted drugs, immunotherapies, and oncolytic virus are discussed in detail. Adjuvant and intensive therapy of HDVC can significantly improve the therapeutic effect of HDVC in the metabolic treatment of cancer, but more clinical evidence is needed to support its clinical application.

Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A. 1976;73:3685–9. https://doi.org/10.1073/pnas.73.10.3685.CrossRefPubMedPubMedCentral

Creagan ET, et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med. 1979;301:687–90. https://doi.org/10.1056/nejm197909273011303.CrossRefPubMed

Moertel CG, et al. 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. N Engl J Med. 1985;312:137–41. https://doi.org/10.1056/nejm198501173120301.CrossRefPubMed

Riordan HD, et al. A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. P R Health Sci J. 2005;24:269–76.PubMed

Poulter JM, White WF, Dickerson JW. Ascorbic acid supplementation and five year survival rates in women with early breast cancer. Acta Vitaminol Enzymol. 1984;6:175–82.PubMed

Bael TE, Peterson BL, Gollob JA. Phase II trial of arsenic trioxide and ascorbic acid with temozolomide in patients with metastatic melanoma with or without central nervous system metastases. Melanoma Res. 2008;18:147–51. https://doi.org/10.1097/CMR.0b013e3282f2a7ae.CrossRefPubMed

Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013;72:139–46. https://doi.org/10.1007/s00280-013-2179-9.CrossRefPubMedPubMedCentral

Cabanillas F. Vitamin C and cancer: what can we conclude–1,609 patients and 33 years later? P R Health Sci J. 2010;29:215–7.PubMed

Nielsen TK, et al. Elimination of ascorbic acid after high-dose infusion in prostate cancer patients: a pharmacokinetic evaluation. Basic Clin Pharmacol Toxicol. 2015;116:343–8. https://doi.org/10.1111/bcpt.12323.CrossRefPubMed

10.

Welsh JL, et al. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol. 2013;71:765–75. https://doi.org/10.1007/s00280-013-2070-8.CrossRefPubMedPubMedCentral

11.

de Grooth HJ, et al. Vitamin C pharmacokinetics in critically Ill patients: a randomized trial of four IV regimens. Chest. 2018;153:1368–77. https://doi.org/10.1016/j.chest.2018.02.025.CrossRefPubMed

12.

Hoffer LJ, et al. High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial. PLoS ONE. 2015;10:e0120228. https://doi.org/10.1371/journal.pone.0120228.CrossRefPubMedPubMedCentral

13.

Shi S, et al. Vitamin C intake and colorectal cancer survival according to KRAS and BRAF mutation: a prospective study in two US cohorts. Br J Cancer. 2023. https://doi.org/10.1038/s41416-023-02452-2.CrossRefPubMedPubMedCentral

14.

Machmouchi A, Chehade L, Temraz S, Shamseddine A. Overcoming EGFR resistance in metastatic colorectal cancer using vitamin C: a review. Biomedicines. 2023. https://doi.org/10.3390/biomedicines11030678.CrossRefPubMedPubMedCentral

15.

Polireddy K, et al. High dose parenteral ascorbate inhibited pancreatic cancer growth and metastasis: mechanisms and a phase I/IIa study. Sci Rep. 2017;7:17188. https://doi.org/10.1038/s41598-017-17568-8.CrossRefPubMedPubMedCentral

16.

Ma Y, et al. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014;6:222ra218. https://doi.org/10.1126/scitranslmed.3007154.CrossRef

17.

Ngo B, Van Riper JM, Cantley LC, Yun J. Targeting cancer vulnerabilities with high-dose vitamin C. Nat Rev Cancer. 2019;19:271–82. https://doi.org/10.1038/s41568-019-0135-7.CrossRefPubMedPubMedCentral

18.

Di Tano M, et al. Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Nat Commun. 2020;11:2332. https://doi.org/10.1038/s41467-020-16243-3.CrossRefPubMedPubMedCentral

19.

Testa U, Pelosi E, Castelli G. New promising developments for potential therapeutic applications of high-dose ascorbate as an anticancer drug. Hematol Oncol Stem Cell Ther. 2021;14:179–91. https://doi.org/10.1016/j.hemonc.2020.11.002.CrossRefPubMed

20.

Wang F, et al. A randomized, open-label, multicenter, phase 3 study of high-dose Vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab in unresectable untreated metastatic colorectal cancer (VITALITY study). Clin Cancer Res. 2022;28:4232–9. https://doi.org/10.1158/1078-0432.Ccr-22-0655.CrossRefPubMedPubMedCentral

21.

Doseděl M, et al. Vitamin C-sources, physiological role, kinetics, deficiency, use, toxicity, and determination. Nutrients. 2021. https://doi.org/10.3390/nu13020615.CrossRefPubMedPubMedCentral

22.

Polidori MC, Mecocci P, Levine M, Frei B. Short-term and long-term vitamin C supplementation in humans dose-dependently increases the resistance of plasma to ex vivo lipid peroxidation. Arch Biochem Biophys. 2004;423:109–15. https://doi.org/10.1016/j.abb.2003.12.019.CrossRefPubMed

23.

Dresen E, et al. History of scurvy and use of vitamin C in critical illness: a narrative review. Nutr Clin Pract. 2023;38:46–54. https://doi.org/10.1002/ncp.10914.CrossRefPubMed

24.

Kaźmierczak-Barańska J, Boguszewska K, Adamus-Grabicka A, Karwowski BT. Two faces of Vitamin C-antioxidative and pro-oxidative agent. Nutrients. 2020. https://doi.org/10.3390/nu12051501.CrossRefPubMedPubMedCentral

25.

Shenoy N, et al. Upregulation of TET activity with ascorbic acid induces epigenetic modulation of lymphoma cells. Blood Cancer J. 2017;7:e587. https://doi.org/10.1038/bcj.2017.65.CrossRefPubMedPubMedCentral

26.

Doskey CM, et al. Tumor cells have decreased ability to metabolize H(2)O(2): implications for pharmacological ascorbate in cancer therapy. Redox Biol. 2016;10:274–84. https://doi.org/10.1016/j.redox.2016.10.010.CrossRefPubMedPubMedCentral

27.

Padayatty SJ, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140:533–7. https://doi.org/10.7326/0003-4819-140-7-200404060-00010.CrossRefPubMed

28.

Hoppe C, Freuding M, Büntzel J, Münstedt K, Hübner J. Clinical efficacy and safety of oral and intravenous vitamin C use in patients with malignant diseases. J Cancer Res Clin Oncol. 2021;147:3025–42. https://doi.org/10.1007/s00432-021-03759-4.CrossRefPubMedPubMedCentral

29.

Fenton HJH. LXXIII.—Oxidation of tartaric acid in presence of iron. J Chem Soc Trans. 1894;65:899–910.CrossRef

30.

Abe C, Miyazawa T, Miyazawa T. Current use of fenton reaction in drugs and food. Molecules. 2022. https://doi.org/10.3390/molecules27175451.CrossRefPubMedPubMedCentral

31.

Stanbury DM. The principle of detailed balancing, the iron-catalyzed disproportionation of hydrogen peroxide, and the Fenton reaction. Dalton Trans. 2022;51:2135–57. https://doi.org/10.1039/d1dt03645a.CrossRefPubMed

32.

Chen HY. Why the reactive oxygen species of the fenton reaction switches from oxoiron(IV) species to hydroxyl radical in phosphate buffer solutions? A computational rationale. ACS Omega. 2019;4:14105–13. https://doi.org/10.1021/acsomega.9b02023.CrossRefPubMedPubMedCentral

33.

Pal S, Jana NR. Pharmacologic vitamin C-based cell therapy via iron oxide nanoparticle-induced intracellular Fenton reaction. ACS Appl Nano Mater. 2020;3:1683–92.CrossRef

34.

Lu HF, Chen HF, Kao CL, Chao I, Chen HY. A computational study of the Fenton reaction in different pH ranges. Phys Chem Chem Phys. 2018;20:22890–901. https://doi.org/10.1039/c8cp04381g.CrossRefPubMed

35.

Gąbka, M. et al. The Membrane Electrical Potential and Intracellular pH as Factors Influencing Intracellular Ascorbate Concentration and Their Role in Cancer Treatment. Cells 10, https://doi.org/10.3390/cells10112964 (2021).

36.

Chen Q, 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. 2008;105:11105–9. https://doi.org/10.1073/pnas.0804226105.CrossRefPubMedPubMedCentral

37.

Duque P, Vieira CP, Bastos B, Vieira J. The evolution of vitamin C biosynthesis and transport in animals. BMC Ecol Evol. 2022;22:84. https://doi.org/10.1186/s12862-022-02040-7.CrossRefPubMedPubMedCentral

38.

Wohlrab C, Phillips E, Dachs GU. Vitamin C Transporters in Cancer: Current Understanding and Gaps in Knowledge. Front Oncol. 2017;7:74. https://doi.org/10.3389/fonc.2017.00074.CrossRefPubMedPubMedCentral

39.

Demiray M. Combinatorial Therapy of High Dose Vitamin C and PARP Inhibitors in DNA Repair Deficiency: A Series of 8 Patients. Integr Cancer Ther. 2020;19:1534735420969812. https://doi.org/10.1177/1534735420969812.CrossRefPubMedPubMedCentral

40.

Giansanti, M., Karimi, T., Faraoni, I. & Graziani, G. High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients. Cancers (Basel) 13, https://doi.org/10.3390/cancers13061428 (2021).

41.

Jankowski CSR, Rabinowitz JD. Selenium Modulates Cancer Cell Response to Pharmacologic Ascorbate. Cancer Res. 2022;82:3486–98. https://doi.org/10.1158/0008-5472.Can-22-0408.CrossRefPubMedPubMedCentral

42.

Lim JY, et al. Vitamin C induces apoptosis in AGS cells via production of ROS of mitochondria. Oncol Lett. 2016;12:4270–6. https://doi.org/10.3892/ol.2016.5212.CrossRefPubMedPubMedCentral

43.

Blaszczak, W. et al. Vitamin C as a Modulator of the Response to Cancer Therapy. Molecules 24, https://doi.org/10.3390/molecules24030453 (2019).

44.

Smith-Cortinez N, et al. Collagen release by human hepatic stellate cells requires vitamin C and is efficiently blocked by hydroxylase inhibition. Faseb j. 2021;35: e21219. https://doi.org/10.1096/fj.202001564RR.CrossRefPubMed

45.

D’Aniello C, Cermola F, Patriarca EJ, Minchiotti G. Vitamin C in Stem Cell Biology: Impact on Extracellular Matrix Homeostasis and Epigenetics. Stem Cells Int. 2017;2017:8936156. https://doi.org/10.1155/2017/8936156.CrossRefPubMedPubMedCentral

46.

Jaakkola P, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–72. https://doi.org/10.1126/science.1059796.CrossRefPubMed

47.

Kawada H, et al. High concentrations of L-ascorbic acid specifically inhibit the growth of human leukemic cells via downregulation of HIF-1α transcription. PLoS ONE. 2013;8: e62717. https://doi.org/10.1371/journal.pone.0062717.CrossRefPubMedPubMedCentral

48.

Fischer AP, Miles SL. Silencing HIF-1α induces TET2 expression and augments ascorbic acid induced 5-hydroxymethylation of DNA in human metastatic melanoma cells. Biochem Biophys Res Commun. 2017;490:176–81. https://doi.org/10.1016/j.bbrc.2017.06.017.CrossRefPubMed

49.

Jóźwiak P, et al. Expression of hypoxia inducible factor 1α and 2α and its association with vitamin C level in thyroid lesions. J Biomed Sci. 2017;24:83. https://doi.org/10.1186/s12929-017-0388-y.CrossRefPubMedPubMedCentral

50.

Kuiper C, Dachs GU, Currie MJ, Vissers MC. Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. Free Radic Biol Med. 2014;69:308–17. https://doi.org/10.1016/j.freeradbiomed.2014.01.033.CrossRefPubMed

51.

Taira A, et al. Vitamin C boosts DNA demethylation in TET2 germline mutation carriers. Clin Epigenetics. 2023;15:7. https://doi.org/10.1186/s13148-022-01404-6.CrossRefPubMedPubMedCentral

52.

Böttger F, Vallés-Martí A, Cahn L, Jimenez CR. High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer. J Exp Clin Cancer Res. 2021;40:343. https://doi.org/10.1186/s13046-021-02134-y.CrossRefPubMedPubMedCentral

53.

Bakalova R, Zhelev Z, Miller T, Aoki I, Higashi T. New potential biomarker for stratification of patients for pharmacological vitamin C in adjuvant settings of cancer therapy. Redox Biol. 2020;28: 101357. https://doi.org/10.1016/j.redox.2019.101357.CrossRefPubMed

54.

Huang, W. Z. et al. Oxidative Status Determines the Cytotoxicity of Ascorbic Acid in Human Oral Normal and Cancer Cells. Int J Mol Sci 24, https://doi.org/10.3390/ijms24054851 (2023).

55.

Cameron, E. & Campbell, A. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact 9, 285–315, https://doi.org/10.1016/0009-2797(74)90019-2 (1974).

56.

Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A. 1978;75:4538–42. https://doi.org/10.1073/pnas.75.9.4538.CrossRefPubMedPubMedCentral

57.

Cameron E, Campbell A. Innovation vs. quality control: an “unpublishable” clinical trial of supplemental ascorbate in incurable cancer. Med Hypotheses. 1991;36:185–9. https://doi.org/10.1016/0306-9877(91)90127-k.CrossRefPubMed

58.

Abou-Jawde RM, et al. Efficacy and safety results with the combination therapy of arsenic trioxide, dexamethasone, and ascorbic acid in multiple myeloma patients: a phase 2 trial. Med Oncol. 2006;23:263–72. https://doi.org/10.1385/MO:23:2:263.CrossRefPubMed

59.

Berenson JR, et al. Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study. Br J Haematol. 2006;135:174–83. https://doi.org/10.1111/j.1365-2141.2006.06280.x.CrossRefPubMed

60.

Wu KL, et al. Phase II multicenter study of arsenic trioxide, ascorbic acid and dexamethasone in patients with relapsed or refractory multiple myeloma. Haematologica. 2006;91:1722–3.PubMed

61.

Berenson JR, et al. A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res. 2007;13:1762–8. https://doi.org/10.1158/1078-0432.CCR-06-1812.CrossRefPubMed

62.

Subbarayan PR, Lima M, Ardalan B. Arsenic trioxide/ascorbic acid therapy in patients with refractory metastatic colorectal carcinoma: a clinical experience. Acta Oncol. 2007;46:557–61. https://doi.org/10.1080/02841860601042456.CrossRefPubMed

63.

Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients’ health-related quality of life after high dose vitamin C administration. J Korean Med Sci. 2007;22:7–11. https://doi.org/10.3346/jkms.2007.22.1.7.CrossRefPubMedPubMedCentral

64.

Hoffer LJ, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. 2008;19:1969–74. https://doi.org/10.1093/annonc/mdn377.CrossRefPubMed

65.

Chang JE, et al. Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: a wisconsin oncology network study. Hematol Oncol. 2009;27:11–6. https://doi.org/10.1002/hon.870.CrossRefPubMedPubMedCentral

66.

Park CH, et al. Depletion of L-ascorbic acid alternating with its supplementation in the treatment of patients with acute myeloid leukemia or myelodysplastic syndromes. Eur J Haematol. 2009;83:108–18. https://doi.org/10.1111/j.1600-0609.2009.01252.x.CrossRefPubMed

67.

Vollbracht C, et al. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany. In Vivo. 2011;25:983–90.PubMed

68.

Welch JS, et al. Combination decitabine, arsenic trioxide, and ascorbic acid for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a phase I study. Am J Hematol. 2011;86:796–800. https://doi.org/10.1002/ajh.22092.CrossRefPubMed

69.

Mikirova N, Casciari J, Rogers A, Taylor P. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J Transl Med. 2012;10:189. https://doi.org/10.1186/1479-5876-10-189.CrossRefPubMedPubMedCentral

70.

Held LA, et al. A Phase I study of arsenic trioxide (Trisenox), ascorbic acid, and bortezomib (Velcade) combination therapy in patients with relapsed/refractory multiple myeloma. Cancer Invest. 2013;31:172–6. https://doi.org/10.3109/07357907.2012.756109.CrossRefPubMed

71.

Nielsen TK, et al. Weekly ascorbic acid infusion in castration-resistant prostate cancer patients: a single-arm phase II trial. Transl Androl Urol. 2017;6:517–28. https://doi.org/10.21037/tau.2017.04.42.CrossRefPubMedPubMedCentral

72.

Bazzan AJ, Zabrecky G, Wintering N, Newberg AB, Monti DA. Retrospective evaluation of clinical experience with intravenous ascorbic acid in patients with cancer. Integr Cancer Ther. 2018;17:912–20. https://doi.org/10.1177/1534735418775809.CrossRefPubMedPubMedCentral

73.

Zhao H, et al. The synergy of Vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia. Leuk Res. 2018;66:1–7. https://doi.org/10.1016/j.leukres.2017.12.009.CrossRefPubMed

74.

Ou J, et al. A randomized phase II trial of best supportive care with or without hyperthermia and vitamin C for heavily pretreated, advanced, refractory non-small-cell lung cancer. J Adv Res. 2020;24:175–82. https://doi.org/10.1016/j.jare.2020.03.004.CrossRefPubMedPubMedCentral

75.

Bahlis NJ, et al. Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma. Clin Cancer Res. 2002;8:3658–68.PubMed

76.

Kawada H, et al. Phase I clinical trial of intravenous L-ascorbic acid following salvage chemotherapy for relapsed B-cell non-Hodgkin’s Lymphoma. Tokai J Exp Clin Med. 2014;39:111–5.PubMed

77.

Jeon Y, Park JS, Moon S, Yeo J. Effect of intravenous high dose Vitamin C on postoperative pain and morphine use after laparoscopic colectomy: a randomized controlled trial. Pain Res Manag. 2016;2016:9147279. https://doi.org/10.1155/2016/9147279.CrossRefPubMedPubMedCentral

78.

Schoenfeld JD, et al. O(2)(⋅-) and H(2)O(2)-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell. 2017;31:487-500 488. https://doi.org/10.1016/j.ccell.2017.02.018.CrossRefPubMedPubMedCentral

79.

Aldoss I, et al. Adding ascorbic acid to arsenic trioxide produces limited benefit in patients with acute myeloid leukemia excluding acute promyelocytic leukemia. Ann Hematol. 2014;93:1839–43. https://doi.org/10.1007/s00277-014-2124-y.CrossRefPubMed

80.

Günes-Bayir A, Kiziltan HS. Palliative Vitamin C application in patients with radiotherapy-resistant bone metastases: a retrospective study. Nutr Cancer. 2015;67:921–5. https://doi.org/10.1080/01635581.2015.1055366.CrossRefPubMed

81.

Jung AY, et al. Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy. Am J Clin Nutr. 2019;109:69–78. https://doi.org/10.1093/ajcn/nqy223.CrossRefPubMed

82.

Kiziltan HS, et al. Ascorbic-acid treatment for progressive bone metastases after radiotherapy: a pilot study. Altern Ther Health Med. 2014;20(Suppl 2):16–20.PubMed

83.

O’Leary BR, et al. Pharmacological ascorbate as an adjuvant for enhancing radiation-chemotherapy responses in gastric adenocarcinoma. Radiat Res. 2018;189:456–65. https://doi.org/10.1667/rr14978.1.CrossRefPubMedPubMedCentral

84.

Wei X, et al. RelB expression determines the differential effects of ascorbic acid in normal and cancer cells. Cancer Res. 2017;77:1345–56. https://doi.org/10.1158/0008-5472.Can-16-0785.CrossRefPubMedPubMedCentral

85.

Prasad KN, Cole WC, Kumar B, Che Prasad K. Pros and cons of antioxidant use during radiation therapy. Cancer Treat Rev. 2002;28:79–91. https://doi.org/10.1053/ctrv.2002.0260.CrossRefPubMed

86.

Castro ML, McConnell MJ, Herst PM. Radiosensitisation by pharmacological ascorbate in glioblastoma multiforme cells, human glial cells, and HUVECs depends on their antioxidant and DNA repair capabilities and is not cancer specific. Free Radic Biol Med. 2014;74:200–9. https://doi.org/10.1016/j.freeradbiomed.2014.06.022.CrossRefPubMed

87.

Alexander MS, et al. Pharmacologic ascorbate reduces radiation-induced normal tissue toxicity and enhances tumor radiosensitization in pancreatic cancer. Cancer Res. 2018;78:6838–51. https://doi.org/10.1158/0008-5472.Can-18-1680.CrossRefPubMedPubMedCentral

88.

Park H, Kang J, Choi J, Heo S, Lee DH. The effect of high dose intravenous Vitamin C during radiotherapy on breast cancer patients’ neutrophil-lymphocyte ratio. J Altern Complement Med. 2020;26:1039–46. https://doi.org/10.1089/acm.2020.0138.CrossRefPubMed

89.

Abdel-Latif MMM, Babar M, Kelleher D, Reynolds JV. A pilot study of the impact of Vitamin C supplementation with neoadjuvant chemoradiation on regulators of inflammation and carcinogenesis in esophageal cancer patients. J Cancer Res Ther. 2019;15:185–91. https://doi.org/10.4103/jcrt.JCRT_763_16.CrossRefPubMed

90.

Furqan M, et al. Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer. Redox Biol. 2022;53:102318. https://doi.org/10.1016/j.redox.2022.102318.CrossRefPubMedPubMedCentral

91.

Monti DA, et al. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS ONE. 2012;7:e29794. https://doi.org/10.1371/journal.pone.0029794.CrossRefPubMedPubMedCentral

92.

Wang F, et al. Phase I study of high-dose ascorbic acid with mFOLFOX6 or FOLFIRI in patients with metastatic colorectal cancer or gastric cancer. BMC Cancer. 2019;19:460. https://doi.org/10.1186/s12885-019-5696-z.CrossRefPubMedPubMedCentral

93.

ClinicalTrials.gov Identifer: NCT04516681. IV ascorbic acid in peritoneal metastatic colorectal cancer.

94.

Darwiche W, et al. Ascorbic acid (Vitamin C) synergistically enhances the therapeutic effect of targeted therapy in chronic lymphocytic leukemia. J Exp Clin Cancer Res. 2020;39:228. https://doi.org/10.1186/s13046-020-01738-0.CrossRefPubMedPubMedCentral

95.

De Francesco EM, Bonuccelli G, Maggiolini M, Sotgia F, Lisanti MP. Vitamin C and doxycycline: a synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs). Oncotarget. 2017;8:67269–86. https://doi.org/10.18632/oncotarget.18428.CrossRefPubMedPubMedCentral

96.

Fiorillo M, Tóth F, Sotgia F, Lisanti MP. Doxycycline, Azithromycin and Vitamin C (DAV): a potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs). Aging. 2019;11:2202–16. https://doi.org/10.18632/aging.101905.CrossRefPubMedPubMedCentral

97.

Vuyyuri SB, et al. Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells. PLoS ONE. 2013;8:e67081. https://doi.org/10.1371/journal.pone.0067081.CrossRefPubMedPubMedCentral

98.

Lee SJ, et al. Effect of high-dose Vitamin C combined with anti-cancer treatment on breast cancer cells. Anticancer Res. 2019;39:751–8. https://doi.org/10.21873/anticanres.13172.CrossRefPubMed

99.

Mustafi S, et al. Vitamin C sensitizes melanoma to BET inhibitors. Cancer Res. 2018;78:572–83. https://doi.org/10.1158/0008-5472.Can-17-2040.CrossRefPubMed

100.

Jung SA, et al. L-Ascorbic acid can abrogate SVCT-2-dependent cetuximab resistance mediated by mutant KRAS in human colon cancer cells. Free Radic Biol Med. 2016;95:200–8. https://doi.org/10.1016/j.freeradbiomed.2016.03.009.CrossRefPubMed

101.

Gordon N, et al. PARP inhibition and pharmacological ascorbate demonstrate synergy in castration-resistant prostate cancer. BioRxiv. 2023. https://doi.org/10.1101/2023.03.23.533944.CrossRefPubMedPubMedCentral

102.

Noordermeer SM, van Attikum H. PARP inhibitor resistance: a tug-of-war in BRCA-mutated cells. Trends Cell Biol. 2019;29:820–34. https://doi.org/10.1016/j.tcb.2019.07.008.CrossRefPubMed

103.

Cimmino L, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. 2017;170:1079-1095.e1020. https://doi.org/10.1016/j.cell.2017.07.032.CrossRefPubMedPubMedCentral

104.

De Francesco EM, Ózsvári B, Sotgia F, Lisanti MP. Dodecyl-TPP targets mitochondria and potently eradicates cancer stem cells (CSCs): synergy with FDA-approved drugs and natural compounds (Vitamin C and Berberine). Front Oncol. 2019;9:615. https://doi.org/10.3389/fonc.2019.00615.CrossRefPubMedPubMedCentral

105.

Bakalova R, et al. Redox-cycling “Mitocans” as effective new developments in anticancer therapy. Int J Mol Sci. 2023. https://doi.org/10.3390/ijms24098435.CrossRefPubMedPubMedCentral

106.

Ivanova D, et al. Vitamin K: redox-modulation, prevention of mitochondrial dysfunction and anticancer effect. Redox Biol. 2018;16:352–8. https://doi.org/10.1016/j.redox.2018.03.013.CrossRefPubMedPubMedCentral

107.

Taper HS. Reversibility of acid and alkaline deoxyribonuclease deficiency in malignant tumor cells. J Histochem Cytochem. 1981;29:1053–60. https://doi.org/10.1177/29.9.7288160.CrossRefPubMed

108.

Verrax J, Taper H, Buc Calderon P. Targeting cancer cells by an oxidant-based therapy. Curr Mol Pharmacol. 2008;1:80–92.CrossRefPubMed

109.

Ren X, et al. The combination of ascorbate and menadione causes cancer cell death by oxidative stress and replicative stress. Free Radic Biol Med. 2019;134:350–8. https://doi.org/10.1016/j.freeradbiomed.2019.01.037.CrossRefPubMed

110.

Tareen B, et al. A 12 week, open label, phase I/IIa study using apatone for the treatment of prostate cancer patients who have failed standard therapy. Int J Med Sci. 2008;5:62–7. https://doi.org/10.7150/ijms.5.62.CrossRefPubMedPubMedCentral

111.

Xu Z, et al. UBIAD1 suppresses the proliferation of bladder carcinoma cells by regulating H-Ras intracellular trafficking via interaction with the C-terminal domain of H-Ras. Cell Death Dis. 2018;9:1170. https://doi.org/10.1038/s41419-018-1215-4.CrossRefPubMedPubMedCentral

112.

Fredericks WJ, et al. Ectopic expression of the TERE1 (UBIAD1) protein inhibits growth of renal clear cell carcinoma cells: altered metabolic phenotype associated with reactive oxygen species, nitric oxide and SXR target genes involved in cholesterol and lipid metabolism. Int J Oncol. 2013;43:638–52. https://doi.org/10.3892/ijo.2013.1985.CrossRefPubMed

113.

Taper HS, et al. In vivo reactivation of DNases in implanted human prostate tumors after administration of a vitamin C/K(3) combination. J Histochem Cytochem. 2001;49:109–20. https://doi.org/10.1177/002215540104900111.CrossRefPubMed

114.

Verrax J, et al. The association of vitamins C and K3 kills cancer cells mainly by autoschizis, a novel form of cell death. Basis for their potential use as coadjuvants in anticancer therapy. Eur J Med Chem. 2003;38:451–7. https://doi.org/10.1016/s0223-5234(03)00082-5.CrossRefPubMed

115.

Taper HS, Keyeux A, Roberfroid M. Potentiation of radiotherapy by nontoxic pretreatment with combined vitamins C and K3 in mice bearing solid transplantable tumor. Anticancer Res. 1996;16:499–503.PubMed

116.

Tomasetti M, et al. alpha-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate. Br J Cancer. 2010;102:1224–34. https://doi.org/10.1038/sj.bjc.6605617.CrossRefPubMedPubMedCentral

117.

Godoy-Pacheco A, et al. Differential modulation of natural killer cell cytotoxicity by 17β-estradiol and prolactin through the NKG2D/NKG2DL axis in cervical cancer cells. Oncol Lett. 2022;24:288. https://doi.org/10.3892/ol.2022.13408.CrossRefPubMedPubMedCentral

118.

Kim JA, Jang JH, Lee SY. An updated comprehensive review on Vitamin A and carotenoids in breast cancer: mechanisms, genetics, assessment, current evidence, and future clinical implications. Nutrients. 2021. https://doi.org/10.3390/nu13093162.CrossRefPubMedPubMedCentral

119.

Peterson CT, Rodionov DA, Osterman AL, Peterson SN. B Vitamins and their role in immune regulation and cancer. Nutrients. 2020. https://doi.org/10.3390/nu12113380.CrossRefPubMedPubMedCentral

120.

Yadav UC, Kalariya NM, Srivastava SK, Ramana KV. Protective role of benfotiamine, a fat-soluble vitamin B1 analogue, in lipopolysaccharide-induced cytotoxic signals in murine macrophages. Free Radic Biol Med. 2010;48:1423–34. https://doi.org/10.1016/j.freeradbiomed.2010.02.031.CrossRefPubMedPubMedCentral

121.

Ma Y, Zhang Y, Zhang H, Wang H, Elmhadi M. Thiamine alleviates high-concentrate-diet-induced oxidative stress, apoptosis, and protects the rumen epithelial barrier function in goats. Front Vet Sci. 2021;8:663698. https://doi.org/10.3389/fvets.2021.663698.CrossRefPubMedPubMedCentral

122.

Ma Y, et al. Thiamine supplementation alleviates lipopolysaccharide-triggered adaptive inflammatory response and modulates energy state via suppression of NFκB/p38 MAPK/AMPK signaling in rumen epithelial cells of goats. Antioxidants (Basel). 2022. https://doi.org/10.3390/antiox11102048.CrossRefPubMedPubMedCentral

123.

Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16:223–49. https://doi.org/10.1146/annurev-pathol-042020-042741.CrossRefPubMed

124.

Makuku R, Khalili N, Razi S, Keshavarz-Fathi M, Rezaei N. Current and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy. J Immunol Res. 2021;2021:6661406. https://doi.org/10.1155/2021/6661406.CrossRefPubMedPubMedCentral

125.

Tang Q, et al. The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol. 2022;13:964442. https://doi.org/10.3389/fimmu.2022.964442.CrossRefPubMedPubMedCentral

126.

Kim CG, et al. Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol. 2021;74:350–9. https://doi.org/10.1016/j.jhep.2020.08.010.CrossRefPubMed

127.

Bedhiafi T, et al. The potential role of vitamin C in empowering cancer immunotherapy. Biomed Pharmacother. 2022;146:112553. https://doi.org/10.1016/j.biopha.2021.112553.CrossRefPubMed

128.

Zaher A, et al. Pharmacological ascorbate as a novel therapeutic strategy to enhance cancer immunotherapy. Front Immunol. 2022;13:989000. https://doi.org/10.3389/fimmu.2022.989000.CrossRefPubMedPubMedCentral

129.

Burkard M, et al. High-dose ascorbate in combination with Anti-PD1 checkpoint inhibition as treatment option for malignant melanoma. Cells. 2023. https://doi.org/10.3390/cells12020254.CrossRefPubMedPubMedCentral

130.

Ashizawa T, et al. Impact of combination therapy with anti-PD-1 blockade and a STAT3 inhibitor on the tumor-infiltrating lymphocyte status. Immunol Lett. 2019;216:43–50. https://doi.org/10.1016/j.imlet.2019.10.003.CrossRefPubMed

131.

Van Damme H, et al. Therapeutic depletion of CCR8(+) tumor-infiltrating regulatory T cells elicits antitumor immunity and synergizes with anti-PD-1 therapy. J Immunother Cancer. 2021. https://doi.org/10.1136/jitc-2020-001749.CrossRefPubMedPubMedCentral

132.

Xie W, et al. Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation. Proc Natl Acad Sci U S A. 2019;116:11946–55. https://doi.org/10.1073/pnas.1905013116.CrossRefPubMedPubMedCentral

133.

Yi M, et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol Cancer. 2022;21:28. https://doi.org/10.1186/s12943-021-01489-2.CrossRefPubMedPubMedCentral

134.

Oduro PK, et al. The cGAS-STING signaling in cardiovascular and metabolic diseases: future novel target option for pharmacotherapy. Acta Pharm Sin B. 2022;12:50–75. https://doi.org/10.1016/j.apsb.2021.05.011.CrossRefPubMed

135.

Corrales L, et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 2015;11:1018–30. https://doi.org/10.1016/j.celrep.2015.04.031.CrossRefPubMedPubMedCentral

136.

Runde AP, Mack R, Breslin SJP, Zhang J. The role of TBK1 in cancer pathogenesis and anticancer immunity. J Exp Clin Cancer Res. 2022;41:135. https://doi.org/10.1186/s13046-022-02352-y.CrossRefPubMedPubMedCentral

137.

Demaria O, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci U S A. 2015;112:15408–13. https://doi.org/10.1073/pnas.1512832112.CrossRefPubMedPubMedCentral

138.

Xu D, Tian Y, Xia Q, Ke B. The cGAS-STING pathway: novel perspectives in liver diseases. Front Immunol. 2021;12:682736. https://doi.org/10.3389/fimmu.2021.682736.CrossRefPubMedPubMedCentral

139.

Qi Z, et al. Identification of prognostic biomarkers and correlations with immune infiltrates among cGAS-STING in hepatocellular carcinoma. 2020. Biosci Rep. https://doi.org/10.1042/bsr20202603.

140.

Zhao X, et al. High dose Vitamin C inhibits PD-L1 by ROS-pSTAT3 signal pathway and enhances T cell function in TNBC. Int Immunopharmacol. 2024;126:111321. https://doi.org/10.1016/j.intimp.2023.111321(2023).CrossRefPubMed

141.

Mondal M, Guo J, He P, Zhou D. Recent advances of oncolytic virus in cancer therapy. Hum Vaccin Immunother. 2020;16:2389–402. https://doi.org/10.1080/21645515.2020.1723363.CrossRefPubMedPubMedCentral

142.

Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642–62. https://doi.org/10.1038/nrd4663.CrossRefPubMedPubMedCentral

143.

Poh A. First oncolytic viral therapy for melanoma. Cancer Discov. 2016;6:6. https://doi.org/10.1158/2159-8290.Cd-nb2015-158.CrossRefPubMed

144.

Keshavarz M, et al. Oncolytic virus delivery modulated immune responses toward cancer therapy: challenges and perspectives. Int Immunopharmacol. 2022;108:108882. https://doi.org/10.1016/j.intimp.2022.108882.CrossRefPubMed

145.

Lv P, et al. Genetically engineered cell membrane nanovesicles for oncolytic adenovirus delivery: a versatile platform for cancer virotherapy. Nano Lett. 2019;19:2993–3001. https://doi.org/10.1021/acs.nanolett.9b00145.CrossRefPubMed

146.

Zhang B, Cheng P. Improving antitumor efficacy via combinatorial regimens of oncolytic virotherapy. Mol Cancer. 2020;19:158. https://doi.org/10.1186/s12943-020-01275-6.CrossRefPubMedPubMedCentral

147.

Li W, et al. Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death. Nat Commun. 2019;10:3349. https://doi.org/10.1038/s41467-019-11269-8.CrossRefPubMedPubMedCentral

148.

Ma J, et al. High-dose VitC plus oncolytic adenoviruses enhance immunogenic tumor cell death and reprogram tumor immune microenvironment. Mol Ther. 2022;30:644–61. https://doi.org/10.1016/j.ymthe.2021.09.015.CrossRefPubMed

149.

Harrington KJ, et al. Clinical development of talimogene laherparepvec (T-VEC): a modified herpes simplex virus type-1-derived oncolytic immunotherapy. Expert Rev Anticancer Ther. 2015;15:1389–403. https://doi.org/10.1586/14737140.2015.1115725.CrossRefPubMed

150.

Santos Apolonio J, et al. Oncolytic virus therapy in cancer: a current review. World J Virol. 2021;10:229–55. https://doi.org/10.5501/wjv.v10.i5.229.CrossRefPubMedPubMedCentral

151.

Su X, et al. Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK/ERK and PI3K/AKT pathways via distinct mechanisms. Theranostics. 2019;9:4461–73. https://doi.org/10.7150/thno.35219.CrossRefPubMedPubMedCentral

152.

Obaid QA, Al-Shammari AM, Khudair KK. Glucose deprivation induced by acarbose and oncolytic newcastle disease virus promote metabolic oxidative stress and cell death in a breast cancer model. Front Mol Biosci. 2022;9:816510. https://doi.org/10.3389/fmolb.2022.816510.CrossRefPubMedPubMedCentral

153.

Magrì A, et al. High-dose Vitamin C enhances cancer immunotherapy. Sci Transl Med. 2020. https://doi.org/10.1126/scitranslmed.aay8707.CrossRefPubMed

154.

Raja J, Ludwig JM, Gettinger SN, Schalper KA, Kim HS. Oncolytic virus immunotherapy: future prospects for oncology. J Immunother Cancer. 2018;6:140. https://doi.org/10.1186/s40425-018-0458-z.CrossRefPubMedPubMedCentral

Titel: High-dose vitamin C as a metabolic treatment of cancer: a new dimension in the era of adjuvant and intensive therapy
verfasst von: Xin Wang
Jia He
Minmin Sun
Shiwan Wang
Jinxiu Qu
Hanping Shi
Benqiang Rao
Publikationsdatum: 11.09.2024
Verlag: Springer International Publishing
Erschienen in: Clinical and Translational Oncology
Print ISSN: 1699-048X
Elektronische ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-024-03553-x

Neu im Fachgebiet Onkologie

Studie zur HIFU bei Prostatakrebs lässt viele Fragen offen

22.01.2025
Prostatakarzinom
Nachrichten

Führt eine HIFU-Ablation beim Prostatakarzinom im Vergleich mit einer radikalen Prostatektomie zu ähnlichen onkologischen, aber besseren funktionalen Ergebnissen? Interimsdaten der französischen HIFI-Studie sind uneindeutig. In einem Kommentar zur Studie werden zumindest drei allgemeine Erkenntnisse herausgearbeitet.

Bei Achalasie auf Candidiasis der Speiseröhre achten!

21.01.2025
Achalasie
Nachrichten

Bei Achalasie-Betroffenen sollte man immer auch auf Candida-Infektionen achten, warnen Forschende aus Rotterdam. In ihrer Studie ließ die Pilzinfektion das Risiko für ein Ösophaguskarzinom massiv steigen.

Adipositas als negativer Prognosefaktor bei Kindern mit Krebs

Eine kanadische Studie weist darauf hin, dass Übergewicht zum Zeitpunkt der Krebsdiagnose ein unabhängiger Risikofaktor für schlechtere Überlebenschancen bei erkrankten Kindern und Jugendlichen sein könnte. Allerdings sind nicht alle Patientinnen und Patienten gleichermaßen betroffen.

Polypen bei nahen Verwandten – erhöhtes Darmkrebsrisiko

20.01.2025
Risikofaktoren für Krebserkrankungen
Nachrichten

Werden bei erstgradigen Verwandten gutartige Darmpolypen identifiziert, ist das Risiko, selbst an einem Kolorektalkarzinom zu erkranken, deutlich erhöht – vor allem das für eine früh beginnende Erkrankung. Hier könnte sich eine frühe Koloskopie besonders lohnen.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen