[摘要]：BACKGROUND & AIMS: Mesalamine has been reported to protect against inflammatory bowel disease-related colorectal cancer (CRC) but several drug-related issues have limited its use in chemopreventive programs. We evaluated the antineoplastic properties OF mesalamine derivatives using in vitro and in vivo models of CRC. METHODS: CRC cell proliferation and cell-cycle progression were evaluated by flow cytometry after exposure to mesalamine or mesalamine derivatives. Cyclins, cyclin-dependent kinases, and endoplasmic reticulum stress-related molecules were examined by immunoblotting. The in vivo antineoplastic effect of 2-methoxy-5-amino-N-hydroxybenzamide (2-14) was evaluated in a syngenic, CT26-derived xenograft Mouse model OF CRC and in the azoxymethane/dextran sulfate sodium-induced mouse model OF colitis-associated CRC. RESULTS: The mesalamine derivative 2-14 was 10-Fold more potent than mesalamine in inhibiting CRC cell proliferation. After exposure to 2-14, cyclin D1 expression was reduced and G0/G1 phase cells accumulated. These events were preceded by activation of eukaryotic translation initiation factor 2-alpha kinase 3 (pancreatic endoplasmic reticulum eIF2 alpha kinase), phosphorylation of eukaryotic translation initiation factor 2alpha, induction of activating transcription Factor 4, and splicing of X-box binding protein 1 messenger RNA, events that define endoplasmic reticulum stress. Silencing of PERK restored cyclin D I levels, allowing cells to overcome the cell-cycle block induced by 2-14. Mice injected with 2-14 developed fewer CRC xenograft-derived tumors. Moreover, 2-14 injection reduced the development OF neoplastic lesions induced by azoxymethane and dextran sulfate sodium In mice. CONCLUSIONS: The mesalamine derivative 2-14 inhibited CRC cell proliferation in vitro and prevented CRC progression in mouse models.
