Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Experimental Chemotherapy Chemotherapy 2012;58:102–109 DOI: 10.1159/000335672 Short-Chain Fatty Acids Induce Apoptosis in Colon Cancer Cells Associated with Changes to Intracellular Redox State and Glucose Metabolism Geoffrey M. Matthews a, b, e Gordon S. Howarth a, c Ross N. Butler a, b, d a Gastroenterology Department, Children, Youth and Women’s Health Service, b Discipline of Physiology, School of Molecular and Biomedical Science and c School of Animal and Veterinary Sciences, University of Adelaide, and d Division of Health Sciences, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, S.A., and e Gene Regulation Laboratory, Cancer Immunology Program, The Peter MacCallum Cancer Institute, Melbourne, Vic., Australia SCFA, induced rapid and extensive apoptosis and G2-M ar- rest 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 chemo- therapy regimens for colon cancer. Copyright © 2012 S. Karger AG, Basel Introduction Colorectal cancer is a major cause of cancer-related death in the Western world [1–4]. It is estimated that up to 70% of colorectal cancers are the result of dietary fac- tors and that a dietary approach to the condition could reduce susceptibility [4, 5]. The fermentation of complex carbohydrates and fiber by anaerobic bacteria, and the subsequent production of short-chain fatty acids (SCFA), particularly butyrate, may play a major role in the modu- latory effect of diet on colonic oncogenesis [6–8]. Indeed, the effects of SCFA in the colon are particularly impor- tant as the concentrations reported to trigger apoptosis, differentiation and cell cycle arrest are readily attained in the colonic lumen in vivo [9]. Previous studies in colon cancer cell lines have docu- mented the induction of apoptosis and cell cycle arrest in G0-G1 or G2-M by butyrate via p53-dependent and p53- Key Words Butyrate  Propionate  Short-chain fatty acid  Colon cancer  Apoptosis  Cell cycle  Redox  Glucose metabolism Abstract 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 re- dox state and glucose metabolism in the Caco-2 human co- lon 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 analy- sis or by isotope ratio mass spectrometry. Results: Butyrate and the SCFA combination induced apoptosis and G2-M ar- rest to a greater extent than propionate alone (p ! 0.05). SCFA treatment led to time-dependent alterations to the ox- idative pentose pathway, reductions in glutathione availabil- ity and increases in levels of reactive oxygen species (p ! 0.05) compared with untreated controls. The rate of D-glu- cose 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 Received: March 15, 2011 Accepted after revision: December 12, 2011 Published online: April 6, 2012 Dr. Geoffrey Matthews Gene Regulation Laboratory, Cancer Immunology Program The Peter MacCallum Cancer Institute, Locked Bag 1, A’Beckett St Melbourne, VIC 8006 (Australia) Tel. +61 3 9656 3724, E-Mail geoff.matthews  @  petermac.org © 2012 S. Karger AG, Basel 0009–3157/12/0582–0102$38.00/0 Accessible online at: www.karger.com/che