Molecular mechanisms of pharmacological doses of ascorbate on cancer cells

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.

Multiple Myeloma Tumor Cells are Selectively Killed by Pharmacologically-dosed Ascorbic Acid

“…Though ROS and H 2 O 2 are well known factors mediating PAA-induced cancer cell death (Espey et al, 2011, Levine et al, 2011), a single molecular mechanism cannot explain these observations because multiple pathways are involved in the downstream effects of ROS and H 2 O 2 (Venturelli et al, 2015). Necorosis, caspase-dependent and caspase-independent apoptosis, and autophagy were reported in ascorbate-induced cell death in different types of cancer (Chen et al, 2015).…”

Ascorbyl palmitate/d-α-tocopheryl polyethylene glycol 1000 succinate monoester mixed micelles for prolonged circulation and targeted delivery of compound K for antilung cancer therapy in vitro and in vivo

“…16,17 Ascorbate has been shown to increase the effectiveness of various anticancer treatments. 18,19 Mixed micelles composed of TPGS and AP are nanosized colloidal particles with a hydrophobic core and a hydrophilic corona. The hydrophobic segment forms the core of the micelles that solubilize the hydrophobic drug molecules, and the hydrophilic segment forms the corona that provides compatibility of the micelles in the aqueous environment.…”

Co-delivery of docetaxel and palmitoyl ascorbate by liposome for enhanced synergistic antitumor efficacy

“…Ascorbate has been well documented to reduce the incidence of most malignancies in humans, but most of the treatments require high-dose ascorbate6789. Recent pharmacological experiment reports have revealed that orally administered ascorbate, even at very large and frequent dose, marginally increases plasma concentrations from 0.07 mM to a maximum of 0.22 mM10.…”