Chemoprevention with Mesalamine – Myth or Reality?

Abstract

Purpose: Patients with ulcerative colitis face an increased risk of developing colorectal carcinoma, the magnitude of risk varying depending on duration and extent of disease. Based on cohort and case-control studies, mesalamine has emerged as a candidate chemopreventive agent. Mesalamine shares close molecular similarity with aspirin and may share chemopreventive properties comparable to aspirin and NSAIDs. The molecular mechanisms involved in potentially reducing cancer risk remain incompletely understood, but limited studies have suggested that mesalamine promotes apoptosis and inhibits proliferation in addition to controlling inflammation. This study examined the effect of mesalamine on 96 genes of a cancer pathway gene array. Methods: Human colon cancer Caco-2 cells were treated with vehicle or mesalamine (4 mM or 40 mM) for 2 and 5 hours. RNA was isolated from the cells and used as templates for hybridization with a cancer pathway gene array. The following studies were performed: (1) mRNA expression by gene array, (2) protein expression by Western blot analysis, and (3) subcellular localization by immunohistochemistry. Results: Two-hour treatment with mesalamine 4 mM and 40 mM downregulated expression of genes encoding transcription factors and signaling transduction molecules such as Akt (∼ 61% and 158%, respectively), c-Ets2 (∼ 74% and 77%, respectively), and c-Myc (∼ 50% and 89%, respectively). In addition, the gene encoding apoptosis regulator Bcl-x was decreased by ∼34% and 89%, respectively. Five-hour treatment with mesalamine 40 mM significantly decreased protein expression of c-Myc ∼ 3 fold (p < 0.05) compared to those cells treated with mesalamine 4 mM or control. Immunohistochemistry demonstrated reduced expression of both Akt and c-Myc. Conclusions: (1) Mesalamine downregulates genes encoding pro-apoptotic factors, transcription factors, and signaling transduction molecules in human colon cancer cells. (2) The apoptotic and growth inhibitory effects of mesalamine are dose-dependent. (3) Expression of c-Myc protein is significantly reduced by high dose mesalamine, whereas it is not significantly affected by standard maintenance dose of mesalamine. This research was funded in part by an unrestricted grant from Proctor&Gamble Pharmaceuticals, Cincinnati, OH.