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Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas
Gut. 2018 Jul;67(7) :1290-1298
PMID: 29122850    PMCID: PMC6031273    URL: https://www.ncbi.nlm.nih.gov/pubmed/29122850
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OBJECTIVE: The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc(+/Min-FCCC) mice with known tumour-bearing status at treatment initiation. DESIGN: Male mice (6-8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both. RESULTS: The multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline (P=0.018) and altered the expression of genes associated with stem/progenitor cells. Treatment of tumour-bearing mice with sulindac/atorvastatin led to a 43% reduction in the multiplicity of colorectal adenomas versus untreated tumour-bearing mice (P=0.049). Sulindac/atorvastatin increased the expression of Hoxb13 and Rprm significantly, suggesting the importance of cell cycle regulation in tumour inhibition. Treatment of SW480 cells with sulindac/atorvastatin led to cell cycle arrest (G0/G1). CONCLUSIONS: The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.
1468-3288 Chang, Wen-Chi L Jackson, Christina Riel, Stacy Cooper, Harry S Devarajan, Karthik Hensley, Harvey H Zhou, Yan Vanderveer, Lisa A Nguyen, Minhhuyen T Clapper, Margie L P30 CA006927/CA/NCI NIH HHS/United States R21 CA129467/CA/NCI NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Gut. 2018 Jul;67(7):1290-1298. doi: 10.1136/gutjnl-2017-313942. Epub 2017 Nov 9.