High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer

Abstract

Mounting evidence indicates that vitamin C has the potential to be a potent anti-cancer agent when administered intravenously and in high doses (high-dose IVC). Early phase clinical trials have confirmed safety and indicated efficacy of IVC in eradicating tumour cells of various cancer types. In recent years, the multi-targeting effects of vitamin C were unravelled, demonstrating a role as cancer-specific, pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator, reversing epithelial-to-mesenchymal transition, inhibiting hypoxia and oncogenic kinase signalling and boosting immune response. Moreover, high-dose IVC is powerful as an adjuvant treatment for cancer, acting synergistically with many standard (chemo-) therapies, as well as a method for mitigating the toxic side-effects of chemotherapy. Despite the rationale and ample evidence, strong clinical data and phase III studies are lacking. Therefore, there is a need for more extensive awareness of the use of this highly promising, non-toxic cancer treatment in the clinical setting. In this review, we provide an elaborate overview of pre-clinical and clinical studies using high-dose IVC as anti-cancer agent, as well as a detailed evaluation of the main known molecular mechanisms involved. A special focus is put on global molecular profiling studies in this respect. In addition, an outlook on future implications of high-dose vitamin C in cancer treatment is presented and recommendations for further research are discussed.

Keywords: Ascorbic acid; Cancer; Clinical trials; IVC; Metabolomics; Proteomics; Transcriptomics; Vitamin C.

Fig. 1

Study overview of pre-clinical, clinical and omics studies using high-dose VitC as anti-cancer agent. Estimated bar graphs of most represented cancer types VitC doses are shown in orange and include high dose (≥ 1 mM in vitro or 1 g/kg in vivo and clinical), medium dose (≤ 0.5 mM in vitro), and low dose (≤ 0.1 mM in vitro,< 1 g/kg in vivo, ≤ 10 g whole body dose clinical). Less represented tumour types are further described in Tables 1, 2, 3 and 4, where oral doses are also included if applicable. Described effect in pre-clinical studies is expressed by percentage of the total number of studies. Reported results in completed clinical trials are expressed by number of studies. Number of studies per global molecular profiling type are also indicated. Omic results include n = 20 in vitro and n = 4 in vivo studies

Fig. 2

Use of high-dose VitC as adjuvant agent in combination with anti-cancer agents. A Described effect of 59 anti-cancer agents combined with high dose vitC investigated in a total of 71 pre-clinical in vitro and in vivo studies (updated may 2021) describing synergy, enhanced efficacy, superior or equivalent effect, reduced toxicity and/or no benefit. B Number of combinations per treatment type. C Described effect per dose group in vitro and in vivo. D Treatment exposure in vitro in hours and frequency dosage in vivo. E Described solvent used for VitC preparation. Use of water stands for MiliQ water, demi water and sterile water; N/S, not specified

Fig. 3

Cancer types investigated in 34 published and 23 ongoing (status February 2021) VitC clinical trials. Annotated are VitC dose group (A and C; high dose ≥1 g/kg, low dose ≤10 g whole body dose) and treatment type (B and D). See Table 2 (medium-to-high-dose published trials; 16/34 of total published trials) and Table 3 (medium-to-high dose ongoing trials; 16/23 of total ongoing trials) for details

Fig. 4

Mechanisms of action described for high-dose VitC in combination with anti-cancer agents in pre-clinical studies. Summary of anti-cancer VitC effects described in vitro and in vivo studies for a total of 45 combinations in the last 5 years (2016–2021). Detailed mechanism of actions per anti-cancer agent are described below. Colour legend corresponds to each mechanism described

Fig. 5

Cancer types studied using global molecular profiling techniques. Annotated are VitC dose group (A; high dose ≥1 mM or 1 g/kg, low dose ≤0.1 mM), type of profiling method used (B) and treatment type (C)

Fig. 6

Overview of high-dose VitC multifaceted cancer effects investigated in pre-clinical and omic studies. Schematic representation of the four most known high-dose VitC modulatory effects in cancer cells and the recently concomitant emerging mechanisms