Apoptosis in colorectal tumour cells: Induction by the short chain fatty acids butyrate, propionate and acetate and by the bile salt deoxycholate

The short chain fatty acids acetate, propionate and butyrate are produced when dietary fibre is fermented by the colonic bacteria. We have previously shown that sodium butyrate induces apoptosis in 3 colorectal tumour cell lines. We have extended our study to 3 adenoma and 4 carcinoma cell lines and investigated whether propionate and acetate also induce apoptosis. All 3 short chain fatty acids induced apoptosis at physiological concentrations, but of the 3, butyrate was the most effective. Since these fatty acids are produced as a result of bacterial fermentation of dietary fibre, this may in part explain the correlation between a high‐fibre diet and low colorectal cancer incidence. Sodium butyrate induced apoptosis in all 7 of the cell lines studied; however, 2 of the 4 carcinoma cell lines (PC/JW/F1 and S/KS/F1) were more resistant to butyrate‐induced apoptosis than the 3 adenoma cell lines, suggesting that at least some carcinomas may evolve mechanisms to protect the cells from the induction of apoptosis. The bile acid deoxycholic acid has previously been reported as a possible tumour promoter in the large intestine and its levels are reduced by dietary fibre. Concentrations of between 10 nM and 0.1 mM had no effect on either the proliferation or apoptosis of colonic tumour cells in vitro. However, a significant induction of apoptosis was obtained at a concentration of 0.5 mM. These results may have significance for the aetiology of colorectal cancer. © 1995 Wiley‐Liss, Inc.

[1]  C. Paraskeva,et al.  Expression of carcinoembryonic antigen by adenoma and carcinoma derived epithelial cell lines: possible marker of tumour progression and modulation of expression by sodium butyrate. , 1988, Carcinogenesis.

[2]  L. Augenlicht,et al.  Potentiation by specific short-chain fatty acids of differentiation and apoptosis in human colonic carcinoma cell lines. , 1994, Cancer research.

[3]  G. Deng,et al.  Transcriptional regulation of the human placental-like alkaline phosphatase gene and mechanisms involved in its induction by sodium butyrate. , 1992, Cancer research.

[4]  C. Marshall,et al.  Specific cytogenetic abnormalities and k‐ras mutation in two new human colorectal‐adenoma‐derived cell lines , 1992, International journal of cancer.

[5]  Gwyn T. Williams,et al.  Activation of Epstein–Barr virus latent genes protects human B cells from death by apoptosis , 1991, Nature.

[6]  A. Wyllie,et al.  Chromatin cleavage in apoptosis: Association with condensed chromatin morphology and dependence on macromolecular synthesis , 1984, The Journal of pathology.

[7]  D. Sheer,et al.  The isolation and characterization of colorectal epithelial cell lines at different stages in malignant transformation from familial polyposis coli patients , 1984, International journal of cancer.

[8]  E. Wynder,et al.  Promoting effect of bile acids on colon carcinogenesis after intrarectal instillation of N-methyl-N'-nitro-N-nitrosoguanidine in rats. , 1974, Journal of the National Cancer Institute.

[9]  W. Roediger Utilization of nutrients by isolated epithelial cells of the rat colon. , 1982, Gastroenterology.

[10]  J. Hickman,et al.  Apoptotic death in epithelial cells: cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. , 1993, The EMBO journal.

[11]  C. Denis-Pouxviel,et al.  Effects of short‐chain fatty acids on growth and differentiation of the human colon‐cancer cell line HT29 , 1992, International journal of cancer.

[12]  B. Drasar,et al.  Bacteria and aetiology of cancer of large bowel. , 1971, Lancet.

[13]  Cummings Jh Colonic absorption: the importance of short chain fatty acids in man. , 1984 .

[14]  T. Kirchner,et al.  Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis. , 1992, Gastroenterology.

[15]  W. Scheppach,et al.  Effects of short chain fatty acids on gut morphology and function. , 1994, Gut.

[16]  C. Cherbut,et al.  Sugar composition of dietary fibre and short-chain fatty acid production during in vitro fermentation by human bacteria , 1993, British Journal of Nutrition.

[17]  G. Macfarlane,et al.  Short chain fatty acids in human large intestine, portal, hepatic and venous blood. , 1987, Gut.

[18]  B. Reddy,et al.  Effect of dietary fiber on colonic bacterial enzymes and bile acids in relation to colon cancer. , 1992, Gastroenterology.

[19]  G. Ronco,et al.  Butyric acid and its monosaccharide ester induce apoptosis in the HL-60 cell line. , 1993, Biochemical and biophysical research communications.

[20]  X. M. Sun,et al.  Key morphological features of apoptosis may occur in the absence of internucleosomal DNA fragmentation. , 1992, The Biochemical journal.

[21]  G. Melino,et al.  Multiple cell cycle access to the apoptotic death programme in human neuroblastoma cells , 1993, FEBS letters.

[22]  A. Manning,et al.  Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53‐independent pathway: Implications for the possible role of dietary fibre in the prevention of large‐bowel cancer , 1993, International journal of cancer.

[23]  B. Vogelstein,et al.  p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. , 1990, Cancer research.

[24]  A. Whittemore,et al.  Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies. , 1992, Journal of the National Cancer Institute.

[25]  J. Kruh Effects of sodium butyrate, a new pharmacological agent, on cells in culture , 1981, Molecular and Cellular Biochemistry.

[26]  C. Paraskeva,et al.  Neoplastic transformation of a human colonic epithelial cell line: in vitro evidence for the adenoma to carcinoma sequence. , 1990, Cancer research.

[27]  A. Wyllie Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation , 1980, Nature.

[28]  Gwyn T. Williams,et al.  Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures , 1989, Nature.

[29]  S. Hakomori,et al.  Antibody-mediated targeting of differentiation inducers to tumor cells: inhibition of colonic cancer cell growth in vitro and in vivo. A preliminary note. , 1989, Biochemical and biophysical research communications.

[30]  R. Whitehead,et al.  Effects of short chain fatty acids on a new human colon carcinoma cell line (LIM1215). , 1986, Gut.

[31]  C. Laboisse,et al.  Emergence of permanently differentiated cell clones in a human colonic cancer cell line in culture after treatment with sodium butyrate. , 1984, Cancer research.

[32]  P. Gibson,et al.  Butyrate production from dietary fibre and protection against large bowel cancer in a rat model. , 1993, Gut.

[33]  K. Khanna,et al.  Butyrate induced apoptosis in lymphoid cells preceded by transient over-expression of HSP70 mRNA. , 1994, Biochemical and biophysical research communications.

[34]  A. Wyllie,et al.  Apoptosis: mechanisms and roles in pathology. , 1991, International review of experimental pathology.

[35]  J. Lupton,et al.  Modulation of colonic epithelial cell proliferation, histone acetylation, and luminal short chain fatty acids by variation of dietary fiber (wheat bran) in rats. , 1992, Cancer research.