The potential of sphingomyelin as a chemopreventive agent in AOM-induced colon cancer model: wild-type and p53+/- mice.
A protective effect of sphingolipids on colorectal cancer (CRC) has been reported in certain mouse strains. It is unknown if sphingolipids are protective in a p53 deficiency mouse model of CRC. This study investigated the effect of sphingomyelin (SM) on intestinal sphingomyelinase (SMase) activity, colonic epithelial biology and azoxymethane (AOM)-induced CRC. Groups of wild-type (C57BL/6J) and p53+/- mice were fed 0.1% SM diet for 4 wk, administered a single AOM injection and then killed 6 h later to measure apoptosis and proliferation. Separately, both mouse types were fed 0.05% SM diet, administered three AOM injections and killed 33-38 wk later to measure tumour formation. SM significantly increased SMase activity and reduced proliferation (p < 0.05) in wild-type and p53+/- mice. SM did not regulate baseline apoptosis, apoptotic response to AOM or apoptosis in tumours, nor did it restore defective apoptosis in p53+/- mice. There was a nonsignificant trend to reduced tumour incidence with SM in wild-type (p = 0.15) and p53+/- (p = 0.12) mice. In conclusion, while increasing intestinal SMase activity and suppressing proliferation, SM did not promote any form of apoptosis and failed to achieve significant protection in these mice. Further investigation to understand the variable effect of SM in preventing CRC is warranted.
Hu
Ying
Y
Department of Medicine, Flinders University of South Australia, Bedford Park, Australia. ying.hu@flinders.edu.au
Le Leu
Richard K
RK
Belobrajdic
Damien
D
Young
Graeme P
GP
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D004249:DNA Damage / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics*
D016588:Anticarcinogenic Agents; D002273:Carcinogens; D013109:Sphingomyelins; D016159:Tumor Suppressor Protein p53; D013108:Sphingomyelin Phosphodiesterase; D001397:Azoxymethane