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 Apcmin/+ 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.

Systems-level biomarkers identification and drug repositioning in colorectal cancer

“…Sulindac treatment resulted in a 58% reduction in polyp count, while sulindac-PC resulted in a 64% reduction. In addition, the researchers confirmed their hypothesis and showed that treatment with sulindac-PC minimized gastrointestinal ulceration compared to treatment with sulindac alone[ 123 ].…”

Dietary Fungal Glucosylceramide and Ceramide Reduce the Formation of Aberrant Crypt Foci in 1,2-Dimethylhydrazine-Treated Mice: Differences in the Role of Glucosylceramide and Ceramide

“…11 Dietary polar lipids, including phosphatidylcholine, protect the gastric mucosa from inflammation in rodents. 30 A decrease in GlcCer levels weakens tight junctions in colonoids. 31 Dietary fungal GlcCer can reach the large intestine; therefore, it may play a role in membrane strengthening of the large intestine.…”

“…One microliter of 6 M HCl and 200 μL of ethanol were added to 50 μL of mice plasma samples and then mixed for 1 min. The mixture was centrifuged twice at 20,000g for 30 Sphingolipids from mice freeze-dried fecal samples were extracted with ethanol as described. 23 The extract (0.40 mL) was added to 0.10 mL of 0.2 M HCl.…”

Perspectives of the Application of Non-Steroidal Anti-Inflammatory Drugs in Cancer Therapy: Attempts to Overcome Their Unfavorable Side Effects

“…Comparatively, the anti-tumoral efficacy of the combination improved from NSAID monotherapy. In several in vivo studies, acetylsalicylic acid, indomethacin, and sulindac combined with PC expressed anti-tumoral activity against colon cancer in mice models [110,111].…”

“…acetylsalicylic acid, indomethacin, and sulindac combined with PC expressed ant moral activity against colon cancer in mice models [110,111].…”