Ascorbate as a Bioactive Compound in Cancer Therapy: The Old Classic Strikes Back

Abstract

Cancer is a disease of high mortality, and its prevalence has increased steadily in the last few years. However, during the last decade, the development of modern chemotherapy schemes, new radiotherapy techniques, targeted therapies and immunotherapy has brought new hope in the treatment of these diseases. Unfortunately, cancer therapies are also associated with frequent and, sometimes, severe adverse events. Ascorbate (ascorbic acid or vitamin C) is a potent water-soluble antioxidant that is produced in most mammals but is not synthesised endogenously in humans, which lack enzymes for its synthesis. Ascorbate has antioxidant effects that correspond closely to the dose administered. Interestingly, this natural antioxidant induces oxidative stress when given intravenously at a high dose, a paradoxical effect due to its interactions with iron. Importantly, this deleterious property of ascorbate can result in increased cell death. Although, historically, ascorbate has been reported to exhibit anti-tumour properties, this effect has been questioned due to the lack of available mechanistic detail. Recently, new evidence has emerged implicating ferroptosis in several types of oxidative stress-mediated cell death, such as those associated with ischemia–reperfusion. This effect could be positively modulated by the interaction of iron and high ascorbate dosing, particularly in cell systems having a high mitotic index. In addition, it has been reported that ascorbate may behave as an adjuvant of favourable anti-tumour effects in cancer therapies such as radiotherapy, radio-chemotherapy, chemotherapy, immunotherapy, or even in monotherapy, as it facilitates tumour cell death through the generation of reactive oxygen species and ferroptosis. In this review, we provide evidence supporting the view that ascorbate should be revisited to develop novel, safe strategies in the treatment of cancer to achieve their application in human medicine.

Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC‐driven lymphoma

“…Indeed, suppressing glutathione synthesis with BSO increased IACS‐010759 activity on MYC‐overexpressing B‐cells and lymphoma cell lines. We further developed this concept by combining IACS‐010759 with ascorbate, which has a pro‐oxidant activity when injected at pharmacological doses and has shown toxicity toward diverse tumor cells (Gonzalez‐Montero et al , 2022 ), including lymphoma (Chen et al , 2005 , 2008 ; Di Tano et al , 2020 ). Remarkably, IACS‐010759 and ascorbate synergized in vitro to kill MYC‐overexpressing B‐cells, owing most likely to the cooperative induction of oxidative damage, including lipid peroxidation and ferroptosis.…”

The Self-Administered Use of Complementary and Alternative Medicine (CAM) Supplements and Antioxidants in Cancer Therapy and the Critical Role of Nrf-2—A Systematic Review

“…Ascorbic acid (vitamin C) is one of the strongest water-soluble antioxidants and its use in adjuvant therapy with anticancer drugs is well documented [ 17 , 142 , 143 ]. Besides numerous studies with cancer cell lines, such as vitamin E, ascorbic acid shows only weak cardio and hepatoprotective effects in rats when treated with DOX (compiled by Granados-Principal et al [ 140 ]).…”

“…In parallel, Nrf-2 activation and nuclear translocation has been observed [ 126 , 148 ]. Interestingly, ongoing clinical trials use high-dose intravenous (IV) vitamin C dosing as monotherapy in several cancers, yet high-quality evidence is missing due to a limited numbers of patients [ 142 ].…”

SERS Tracking Oxidative Stress on a Metalloporphyrin Framework by Vitamin C

“…10−13 By combining VC and some targeted medicines acting on enzymes, the antitumor therapeutic effect can be improved. 14 Therefore, the in situ monitoring of this enzyme catalytic process is of great significance for studying the role of VC in oxidative stress and cancer treatment in vivo.…”

“…However, it has been considered that VC with a certain pharmacological concentration (0.3–20 mM) can produce H 2 O 2 -dependent cytotoxicity to a variety of cancer cells, which is conducive to antitumor treatment. , It is believed that this selective toxic effect of cancer is related to the Fenton reaction of cells. After the Fenton reaction of a metal cofactor catalyzed by VC, H 2 O 2 is converted into the highly oxidized hydroxyl radical (•OH), which causes serious oxidative stress. − By combining VC and some targeted medicines acting on enzymes, the antitumor therapeutic effect can be improved . Therefore, the in situ monitoring of this enzyme catalytic process is of great significance for studying the role of VC in oxidative stress and cancer treatment in vivo.…”