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Molecular mechanisms of pharmacological doses of ascorbate on cancer cells

Über die molekularen Wirkmechanismen pharmakologischer Dosierungen von Vitamin C gegenüber Tumorzellen

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Abstract

Intravenous application of high-dose ascorbate (vitamin C) has been used in complementary medicine since the 1970s to treat cancer patients. In recent years it became evident that high-dose ascorbate in the millimolar range bears selective cytotoxic effects on cancer cells in vitro and in vivo. This anticancer effect is dose dependent, catalyzed by serum components and mediated by reactive oxygen species and ascorbyl radicals, making ascorbate a pro-oxidative pro-drug that catalyzes hydrogen peroxide production in tissues instead of acting as a radical scavenger. It further depends on HIF-1 signaling and oxygen pressure, and shows a strong epigenetic signature (alteration of DNA-methylation and induction of tumor-suppressing microRNAs in cancer cells). The detailed understanding of ascorbate-induced antiproliferative molecular mechanisms warrants in-depth preclinical evaluation in cancer-bearing animal models for the optimization of an efficacious therapy regimen (e.g., combination with hyperbaric oxygen or O2-sensitizers) that subsequently need to be evaluated in clinical trials.

Zusammenfassung

Die intravenöse Hochdosis-Vitamin C Therapie wird seit über 30 Jahren in der Komplementärmedizin als unterstützende Behandlung von Krebspatienten angewendet. Pharmakologische Dosen von Vitamin C im Millimolarbereich wirken in vitro und in vivo selektiv toxisch auf Krebszellen. Diese Krebszellen-tötenden Eigenschaften werden durch Serumkomponenten katalysiert und durch H2O2 und Ascorbyl-Radikale vermittelt, so dass Vitamin C dosisabhängig im Tumorgewebe als pro-oxidatives Molekül fungiert und nicht als Radikalfänger. Weiterhin werden die pharmakologischen Eigenschaften von Vitamin C durch die HIF-1 Signaltransduktionskaskade und den O2-Partialdruck maßgeblich beeinflusst und wirken zusätzlich auf epigenetischer Ebene über Modifizierung der DNA-Methylierung und Induktion von Tumor-supprimierenden microRNAs. Aus dem heutigen Verständnis des komplexen molekularen Wirkmechanismus von Vitamin C gegenüber Krebszellen erschließt sich die Notwendigkeit der Optimierung des Therapieschemas in geeigneten Tiermodellen (z. B. in Kombination mit hyperbarer Sauerstofftherapie oder gewebegängigen O2-Liberatoren), um die rasche Übertragung einer effektiven Hochdosis-Vitamin C Therapie für Krebspatienten in die Klinik zu ermöglichen.

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Acknowledgments

This work was supported by grants from the DFG SFB 773: “Understanding and overcoming drug resistance of solid tumors” to C. Busch. S. Venturelli was supported by the Innovation Grant of the University Tuebingen, Else Uebelmesser Foundation and German Childhood Cancer Foundation (DKS). T. W. Sinnberg was supported by the fortuene program of the University Clinic Tuebingen (2198-0-0). C. Busch and S. Venturelli received a research grant from the Wissenschaftsfoerderung der Deutschen Brauwirtschaft e. V. (B103) and Pascoe pharmazeutische Praeparate GmbH.

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The sponsors had no involvement in the study design, in the collection, analysis and interpretation of data, in the writing of the manuscript and in the decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany

    Sascha Venturelli

  2. Division of Dermatologic Oncology, Department of Dermatology and Allergology, University Hospital of Tuebingen, Liebermeisterstr. 25, 72076, Tuebingen, Germany

    Tobias W. Sinnberg, Heike Niessner &  Christian Busch

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  1. Sascha Venturelli
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  2. Tobias W. Sinnberg
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  4. Christian Busch
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Correspondence to Christian Busch.

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Venturelli, S., Sinnberg, T., Niessner, H. et al. Molecular mechanisms of pharmacological doses of ascorbate on cancer cells. Wien Med Wochenschr 165, 251–257 (2015). https://doi.org/10.1007/s10354-015-0356-7

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