N‐palmitoyl‐d‐glucosamine limits mucosal damage and VEGF‐mediated angiogenesis by PPARα‐dependent suppression of pAkt/mTOR/HIF1α pathway and increase in PEA levels in AOM/DSS colorectal carcinoma in mice

Abstract

AbstractChronic intestinal inflammation and neo‐angiogenesis are interconnected in colorectal carcinoma (CRC) pathogenesis. Molecules reducing inflammation and angiogenesis hold promise for CRC prevention and treatment. N‐Palmitoyl‐d‐glucosamine (PGA), a natural glycolipid analog with anti‐inflammatory properties, has shown efficacy against acute colitis. Micronized PGA (mPGA) formulations exhibit superior anti‐inflammatory activity. This study investigates the in vivo anti‐angiogenic and protective effects of mPGA in a mouse model of colitis‐associated CRC induced by azoxymethane/dextran sodium sulfate (AOM/DSS). CRC was induced in C57BL/6J mice using intraperitoneal azoxymethane followed by three cycles of 2.5% dextran sodium sulfate (DSS) in drinking water. Mice were treated with mPGA (30–150 mg/kg) with or without the PPARα inhibitor MK886 (10 mg/kg). At Day 70 post‐azoxymethane injection, mice underwent anesthetized endoscopic colon evaluation. Post‐mortem analysis of tumorigenesis and angiogenesis was performed using histological, immunohistochemical, and immunoblotting techniques. mPGA improved disease progression and survival rates in a dose‐ and PPARα‐dependent manner in AOM/DSS‐exposed mice. It reduced polyp formation, decreased pro‐angiogenic CD31, pro‐proliferative Ki67, and pro‐inflammatory TLR4 expression levels, and inhibited VEGF and MMP‐9 secretion by disrupting the pAkt/mTOR/HIF1α pathway. mPGA increased colon PEA levels, restoring anti‐tumoral PPARα and wtp53 protein expression. Given its lack of toxicity, mPGA shows potential as a nutritional intervention to counteract inflammation‐related angiogenesis in CRC.