The impact of anti-inflammatory drug sulindac on obesity-associated colon tumor growth
Creators: name: Punjala, Arunima
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2018

description: AbstractBackground: Obesity is a known risk factor for colon cancer, the second leading cause of cancer death in the United States. Excess visceral adipose tissue (VAT) associated with obesity stimulates pro-inflammatory and pro-tumorigenic signaling pathways that increases the risk for colon cancer. In this study we examine whether weight loss and/or treatment with the non-steroidal anti-inflammatory drug sulindac reduces obesity-associated tumor growth in a mouse model of colon tumorigenesis.Methods: 10-week old male FVB mice (n=130) were given a chemical carcinogen, azoxymethane (10 mg/kg i.p.), for 5 weeks. Afterwards, the mice were randomized to a control (10% kcal from fat) or diet-induced obesity (DIO, 60% kcal from fat) diet for 15 weeks. Following an interim sacrifice of 5 mice/group, the DIO mice were further randomized to continue a DIO diet or switch to a control diet to induce weight loss and become formerly obese mice (FOb). Within each diet group (control, DIO, FOb) half the mice were randomized to receive sulindac supplementation (140 ppm in the diet). Eight weeks later, all mice were euthanized and tissues collected for analysis. Colon tumor gene expression was analyzed via microarray.Results: The DIO mice, compared to controls, had significantly greater final body weight and body fat levels (P<0.05), while FOb mice had intermediate levels of adiposity. Treatment with sulindac did not affect final body weight or body fat percentage compared to groups that did not receive treatment. At interim sacrifice, DIO mice had a 2-fold greater tumor incidence and a 10-fold greater tumor burden compared to control mice. Across all groups, sulindac reduced tumor incidence, and in DIO and control mice, but not FOb mice, sulindac significantly reduced tumor burden (P<0.05). Several serum cytokines, including IL-6, CXCL1, VEGF, MCP-1, and G-CSF, were significantly elevated in DIO mice without sulindac treatment compared to control mice (P<0.05), but did not differ between FOb and control mice. Sulindac treatment significantly reduced serum levels of these proteins in DIO mice (P<0.05). Several adipokines, including leptin and PAI-1, were significantly increased in DIO mice in comparison to control and FOb mice (P<0.05). Sulindac treatment did not significantly reduce serum levels of these hormones in any of the diet groups. Tumor expression of matrix metalloproteinases and several genes involved in focal adhesion pathways was significantly higher in DIO mice versus the FOb and DIO + sulindac mice (P<0.05). Ccl21 expression was significantly increased by sulindac treatment in DIO mice (P<0.05) but not affected by weight loss.Conclusions: Weight loss and sulindac treatment completely reversed the effects of obesity on colon tumorigenesis, the latter without any change in adiposity. Tumoral gene expression suggests that these two interventions share some common anti-tumor mechanisms, but also may act through additional mechanisms specific to each intervention. Our findings indicate that research regarding the effects of NSAID treatment on colon cancer risk and/or progression in obese patients is warranted, especially in those who are unable to achieve moderate weight loss.