Sulindac plus a phospholipid is effective for polyp reduction and safer than sulindac alone in a mouse model of colorectal cancer development

Abstract

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and sulindac are effective for colorectal cancer prevention in humans and some animal models, but concerns over gastro-intestinal (GI) ulceration and bleeding limit their potential for chemopreventive use in broader populations. Recently, the combination of aspirin with a phospholipid, packaged as PL-ASA, was shown to reduce GI toxicity in a small clinical trial. However, these studies were done for relatively short periods of time. Since prolonged, regular use is needed for chemopreventive benefit, it is important to know whether GI safety is maintained over longer use periods and whether cancer prevention efficacy is preserved when an NSAID is combined with a phospholipid.

Methods: As a first step to answering these questions, we treated seven to eight-week-old, male and female C57B/6 Apc^min/+ mice with the NSAID sulindac, with and without phosphatidylcholine (PC) for 3-weeks. At the end of the treatment period, we evaluated polyp burden, gastric toxicity, urinary prostaglandins (as a marker of sulindac target engagement), and blood chemistries.

Results: Both sulindac and sulindac-PC treatments resulted in significantly reduced polyp burden, and decreased urinary prostaglandins, but sulindac-PC treatment also resulted in the reduction of gastric lesions compared to sulindac alone.

Conclusions: Together these data provide pre-clinical support for combining NSAIDs with a phospholipid, such as phosphatidylcholine to reduce GI toxicity while maintaining chemopreventive efficacy.

Keywords: Chemoprevention; Colorectal cancer; Gastrointestinal safety; Polyps; Sulindac.

Fig. 1

Sulindac and Sulindac-PC are effective at reducing polyp burden. a Total intestinal polyp number by treatment group No Treatment (○), PBS (□), PC (∆), Sulindac (), Sulindac-PC (◊), groups with different letters are significantly different from each other. Each point represents data from an individual mouse. b Percent reduction in polyp count compared to No Treatment group. c Total intestinal polyp area by treatment group d Percent of polyps are shown by size category and treatment group, groups with different letters have significantly different proportions of 1.0–2.0 mm polyps. Columns = average, bars = standard error of the mean, N = 6–7 mice per treatment group, each symbol represents one mouse e Representative images of polyp annotations. Tissues are shown without (top) and with (bottom) polyps annotated (*). Arrow indicates a Peyer’s patch. Scale bar = 1000 μm

Fig. 2

Treatment with Sulindac-PC results in significantly less gastric toxicity compared to Sulindac. a Gastric Inflammation by treatment. b Hyperplasia of the glandular epithelium by treatment. c Ulcer Prevalence by treatment. d Example images of scored lesions, arrows indicate specified lesions. Scale bar = 500 μm. No Treatment (○), PBS (□), PC (∆), Sulindac (), Sulindac-PC (◊)

Fig. 3

Sulindac and Sulindac-PC show biological activity. a Nuclear β-catenin IHC scores by treatment (left) and percent lesions at each staining level (right) columns = mean, bars = standard error. Groups with different letters are significantly different from each other b Representative images of β-catenin staining and localization within polyps. Scale bar = 50 μm. c End of study urinary prostaglandin profiles by treatment group. No Treatment (○), PBS (□), PC (∆), Sulindac (), Sulindac-PC (◊)