Short-Chain Fatty Acids Induce Apoptosis in Colon Cancer Cells Associated with Changes to Intracellular Redox State and Glucose Metabolism

Background: Short-chain fatty acids (SCFA) are undergoing increased scrutiny as chemotherapeutics for colon cancer, although a comprehensive understanding of their mode of action is lacking. We investigated candidate SCFA for their capability to modulate apoptosis, cell cycle, intracellular redox state and glucose metabolism in the Caco-2 human colon cancer cell line. Methods: Caco-2 cells were incubated with butyrate, propionate or a combination of these SCFA (1:1) and assessed by flow cytometry, enzyme activity analysis or by isotope ratio mass spectrometry. Results: Butyrate and the SCFA combination induced apoptosis and G2-M arrest to a greater extent than propionate alone (p < 0.05). SCFA treatment led to time-dependent alterations to the oxidative pentose pathway, reductions in glutathione availability and increases in levels of reactive oxygen species (p < 0.05) compared with untreated controls. The rate of D-glucose metabolism was increased by all SCFA, although to the greatest extent by butyrate (p < 0.05). Conclusions: These results suggest that butyrate, or the combination of both SCFA, induced rapid and extensive apoptosis and G2-M arrest associated with changes to redox state and D-glucose metabolism. These results support the potential for butyrate and propionate to act as adjuncts to conventional chemotherapy regimens for colon cancer.