Molecular Alterations Associated with Sulindac-Resistant Colon Tumors in ApcMin/+ Mice

Abstract

Although nonsteroidal anti-inflammatory drugs (NSAID), including sulindac, have been used extensively as chemopreventive agents for colorectal cancer, results are not consistent. NSAIDs, most reportedly sulindac, often do not cause a complete regression of adenomas and some patients develop resistance to NSAID treatment. In this study, we evaluated the effect of sulindac on colon tumorigenesis in the Apc Min/+ mouse model. Sulindac (180 ppm) given in drinking water for 9 weeks to Apc Min/+ mice significantly reduced the size of colon tumors, but actually caused an increase in colon tumor multiplicity relative to untreated controls (average of 5.5 versus 1.6 tumors per mouse, respectively; P < 0.0001). This indicated that the drug could inhibit colon tumor progression but not initiation. As expected, in the small intestine, sulindac significantly reduced tumor size and multiplicity relative to untreated controls (average of 2.3 versus 42.0 tumors per mouse, respectively; P < 0.0001). Generation of a panel of prostanoids was comparably suppressed in the small intestine and colon by sulindac treatment. Sulindac is also known to exert its growth inhibitory effects through regulation of many noncyclooxygenase targets, including p21, β-catenin, E-cadherin, mitochondrial apoptotic proteins, and peroxisome proliferator-activated receptor-γ. We found that sulindac treatment protected against E-cadherin loss in colon tumors, with associated inhibition of nuclear β-catenin accumulation. Importantly, p21 WAF1/cip1 and peroxisome proliferatoractivated receptor-γ expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. Together, these observations may be translatable to designing novel clinical therapies using combinations of agents that target multiple molecular pathways to overcome sulindac resistance. Cancer Prev Res; 3(9);

CXCR2 inhibition enhances sulindac‐mediated suppression of colon cancer development

“…To address this possibility, Apc min/+ /CXCR2 WT and Apc min/+ /CXCR2 Het littermates were treated with a low‐dose sulindac (10 mg/kg/day) through a buffered drinking water for 9‐weeks from day 28 to 91 of their ages. Of note, many previous studies have used sulindac at doses higher than 20 mg/kg/day . While sulindac treatment and a single copy deletion of CXCR2 alone reduced total number of polyps in the small intestine by 31% and 19%, respectively, the combined conditions reduced the intestinal polyp formation by 57% (Fig.…”

“…b ). We attribute this to the overall inefficiency in APC min ‐induced polyp formation in the large intestine, compared to the small intestine . We next studied the molecular mechanism underlying the inhibition of APC min ‐induced tumor formation by CXCR2 deletion.…”

Selective PGE2 Suppression Inhibits Colon Carcinogenesis and Modifies Local Mucosal Immunity

“…To evaluate this possibility, colon tumors were examined immunohistochemically for PCNA staining (proliferation), and cleaved caspase-3, which detects an earlier stage of apoptosis in cells that have not yet undergone major morphological changes (14). A total of 10 colons from each genotype were selected for IHC analyses.…”

Intestinal inflammatory cytokine response in relation to tumorigenesis in the ApcMin/+ mouse

“…It has been shown to be responsive to treatment with anti-inflammatory agents, including both anti-inflammatory dietary supplements as well as non-steroidal anti-inflammatory drugs (NSAIDs) [19]. For example, Greenspan et al reported that the NSAID Sulindac can decrease intestinal polyp number in the Apc Min/+ mouse that is associated with a decrease in proliferative and inflammatory prostaglandins in the small intestine and colon [27]. Similarly, another study reported that Celecoxib reduced the formation of intestinal polyps that was associated with lower levels of COX-2 activity [28].…”