Ascorbic Acid in Cancer Treatment: Let the Phoenix Fly

Abstract

Vitamin C (ascorbic acid, ascorbate), despite controversy, has re-emerged as a promising anti-cancer agent. Recent knowledge of intravenous ascorbate pharmacokinetics and discovery of unexpected mechanisms of ascorbate action have spawned many investigations. Two mechanisms of anti-cancer activity with ascorbate have gained prominence: hydrogen peroxide-induced oxidative stress and DNA demethylation mediated by ten-eleven translocation enzyme activation. Here, we highlight salient aspects of the evolution of ascorbate in cancer treatment, provide insights into the pharmacokinetics of ascorbate, describe mechanisms of its anti-cancer activity in relation to the pharmacokinetics, outline promising preclinical and clinical evidence, and recommend future directions.

High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model

“…In addition, it is possible that the changes observed in HERV expression could also be mediated by nonmethylation mechanisms. Of note, AA has been shown to have anticancer activity in immunocompromised mouse models, indicating the additional importance of non-immune-mediated mechanisms of action such as oxidative stress, epigenetic reprogramming of cancer cells and the varied cofactor functions of AA (9,17,(41)(42)(43)(44)(45). Given these additional potential contributing mechanisms, we felt that conventional DNMT inhibitors would not serve as appropriate enough controls to justify their inclusion in the in vivo study (and killing 20 more mice), particularly given that the combination of DNMT inhibitors and checkpoint blockade is already being investigated in the clinical setting.…”

“…In contrast, effects of DNMTIs on immune cells are inconsistent, with some studies indicating an inhibitory effect (3,(13)(14)(15)(16). Importantly, high-dose AA has been shown to be a promising anticancer agent in early-phase clinical trials and is not only well tolerated but appears to decrease the side effects of chemotherapy (17).…”

A chirality‐dependent action of vitamin C in suppressing Kirsten rat sarcoma mutant tumor growth by the oxidative combination: Rationale for cancer therapeutics

“…An elevated glucose consumption rate by these highly malignant cancer cells is likely to impose a metabolic state that is sensitive to oxidative stress. The indicated working concentration of VC at 1 mM concentration does not limit a potential clinical application of the ATO and VC combination because the intravenous VC administration bypassed limitation of its oral administration by increasing the drug dosage 100 times and by reaching maximum safe administration of VC to 10 mM . Importantly, we found a remarkable difference in efficacy between the l ‐VC and d ‐VC enantiomers when they were combined with ATO in the xenograft mouse model, while both combinations showed similar potency according to the cell culture study.…”

“…The indicated working concentration of VC at 1 mM concentration does not limit a potential clinical application of the ATO and VC combination because the intravenous VC administration bypassed limitation of its oral administration by increasing the drug dosage 100 times and by reaching maximum safe administration of VC to 10 mM. 25 Importantly, we found a remarkable difference in efficacy between the L-VC and D-VC enantiomers when they were combined with ATO in the xenograft mouse model, while both combinations showed similar potency according to the cell culture study. This finding suggests that both VC isomers use a similar mechanism in KRAS mutant cancer cells via provoking an oxidative stress but the distinctive pharmacokinetics of D-VC made it more superior to its natural L-VC form in the animal model.…”

Vitamin C versus Cancer: Ascorbic Acid Radical and Impairment of Mitochondrial Respiration?

“…If vitamin C can clinically exploit the pathway presented here, we suggest it offers a new, exciting rationale for cancer studies. Perhaps this orthogonal mechanism of action can safely and more effectively compliment current cancer treatments in the adjuvant setting and help to let the phoenix fly [94].…”