Differential preventive activity of sulindac and atorvastatin in Apc^+/Min-FCCCmice with or without colorectal adenomas

Abstract

ObjectiveThe 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.DesignMale 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.ResultsThe 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).ConclusionsThe 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.

Aspirin alone and combined with a statin suppresses eicosanoid formation in human colon tissue

“…Furthermore, we believe the question of relative contribution of COX-1 and COX-2 activity to the PGE 2 formation to be critical for the assessment of aspirin's anti-tumor effect in different stages of prevention, i.e., in the context of normal noninflamed mucosa (as in this study), or in the context of adenoma progression toward colorectal carcinoma. In this regard, recent observations in an established murine CRC model impressively revealed the significance of the tumor status on the time of treatment initiation for the efficacy of chemopreventive agents against adenoma formation (60).…”

Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors

“…Moreover, the combination failed to inhibit progression in those with advanced adenomas or colon cancer. A clinical assessment of the NSAID/statin duo in combination with a chemotherapeutic agent has not yet been conducted in humans but has shown promise in animal models [57].…”

“…Certain medications that are commonly prescribed for other conditions, such as NSAIDs, statins, and bisphosphonates have been shown to protect against CRC, especially when used in combination. These compounds may also facilitate the treatment of CRC in combination with chemotherapeutic agents [57–60]. However, due to the limited data available and possible side-effects, these medications are not recommended to the general public simply for the prevention of CRC.…”

The Reprimo Gene Family: A Novel Gene Lineage in Gastric Cancer with Tumor Suppressive Properties

“…Clinical studies have shown that the loss of RPRM expression is as common event in gastric cancer [ 3 , 31 , 32 , 36 ] as in other tumors of the gastrointestinal tract including Barrett’s-associated esophageal adenocarcinoma, pancreatic and colorectal carcinoma [ 37 , 38 , 39 , 40 , 41 ]. Loss of expression of RPRM has been also reported in non-digestive tumors including breast, renal cell carcinoma, adrenocortical and pituitary tumors [ 33 , 34 , 35 , 42 , 43 ].…”