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Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas

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-F...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031273/
https://www.ncbi.nlm.nih.gov/pubmed/29122850
http://dx.doi.org/10.1136/gutjnl-2017-313942
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author 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
author_facet 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
author_sort Chang, Wen-Chi L
collection PubMed
description 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.
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spelling pubmed-60312732018-07-06 Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas 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 Gut Colon 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. BMJ Publishing Group 2018-07 2017-11-09 /pmc/articles/PMC6031273/ /pubmed/29122850 http://dx.doi.org/10.1136/gutjnl-2017-313942 Text en © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
spellingShingle Colon
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
Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas
title Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas
title_full Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas
title_fullStr Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas
title_full_unstemmed Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas
title_short Differential preventive activity of sulindac and atorvastatin in Apc(+/Min-FCCC)mice with or without colorectal adenomas
title_sort differential preventive activity of sulindac and atorvastatin in apc(+/min-fccc)mice with or without colorectal adenomas
topic Colon
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031273/
https://www.ncbi.nlm.nih.gov/pubmed/29122850
http://dx.doi.org/10.1136/gutjnl-2017-313942
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