(P06-030-23) Gastroprotective [6]-Gingerol Aspirinate as a Novel Chemopreventive Prodrug of Aspirin To Attenuate Colitis

Objectives: Studies suggests that daily low-dose aspirin (ASA) could prevent cardiovascular disease and colorectal cancer in high-risk patients. However, the side effects in the gastrointestinal tract limit its use. Preclinical studies have shown that ginger constituents can alleviate ASA-induced gastric ulceration. We developed a novel prodrug of ASA, [6]-gingerol aspirinate (GAS), which combines the ginger ingredient [6]-gingerol (6G) and ASA in one molecule. Our study aims to investigate the anti-cancer effects in cells, the gastroprotective ability and its effects against dextran sodium sulfate (DSS)-induced colitis in mice.

Methods: The metabolism of GAS was analyzed using LC/MS. The gastroprotective effect was tested on mice with stomach. The anti-cancer properties were determined using MTT assay and colony formation assay. The colitis model was induced by 2.5% DSS treatment for 5 days and followed by water for 7 days to allow for recovery. Mice in the treated groups were pretreated with GAS or ASA for two weeks. The inflammatory biomarkers were measured using ELISA kit and Western blot. 

Results: Our findings demonstrate that GAS can withstand the harsh acidic environment of the stomach, followed by complete decomposition in the distal intestine to release 6G and ASA. This indicate that GAS has the potential to prevent gastrointestinal bleeding induced by ASA. This notion is supported by our observation that GAS significantly inhibited the stomach injury in mice by 75% and has better protective effects on stomach mucosa. In addition, our results demonstrated that GAS was more active to against the growth of human colon cancer cells and inhibit colony formations in a dose-dependent manner. GAS also exerted significantly inhibitory effects towards COX-1 and COX-2. Moreover, in a colitis model, GAS treatment improved colitis symptoms and reduced elevated pro-inflammatory cytokines induced by DSS, including IL-6, TNF-α, IL-1β, and TGF-β, while ASA treatment did not have the same effect.

Conclusions: Our results indicate that GAS has anticancer activities and provides significant gastroprotective effects when compared to plain ASA. Additionally, our study also demonstrates the chemoprevention of dietary GAS against colitis. These findings suggest GAS may be a safer and more effective ASA prodrug.

Funding Sources: Grant CA159353 from the National Cancer Institute