Ascorbic Acid in Colon Cancer: From the Basic to the Clinical Applications

Abstract

Given the safety and potential benefits of intravenous ascorbic acid (AA) administration in cancer patients, there is merit in further exploring this therapeutic concept. In this review, we discuss the potential benefits of intravenous AA administration on colorectal cancer and we specifically focus on its effect on glycolysis in mutant and wild type RAS. We perform a PubMed and Ovid MEDLINE search using ascorbic acid, intravenous vitamin C, KRAS mutation, BRAF mutation and colorectal cancer (CRC) as keywords. At the cellular level, colorectal cancer cells undergo a metabolic shift called the Warburg effect to allow for more glucose absorption and utilization of glycolysis. This shift also allows AA to enter which leads to a disruption in the Warburg effect and a shutdown of the downstream KRAS pathway in mutated KRAS colon cancer cells. At the clinical level, AA is associated with tumour regression in advanced disease and improved tolerability and side effects of standard therapy. Based on these findings, we conclude that further clinical trials are needed on a larger scale to examine the therapeutic benefits of AA in colon cancer.

Keywords: AA; CRC; cell lines; vitamin C.

Figure 1

Effect of ascorbic acid (AA) on KRAS mutant colon cells. Upon entry into the cell, dehydroascorbate (DHA) is reduced to AA which has two effects: (1) RAS detachment from the cell membrane which inhibits the downstream phosphorylation cascade (MEK/ERK/PKM2) which, in turn, inhibits GLUT-1 expression; and (2) glutathione depletion during the reduction process leads to accumulation of reactive oxygen species (ROS), which leads to the inactivation of GAPDH. These two effects inhibit glycolysis in cells that are highly dependent on energy, leading to an energy crisis and cell death. The effect of vitamin C is denoted in red.