Inhibition of colon carcinogenesis by 2-methoxy-5-amino-N-hydroxybenzamide, a novel derivative of mesalamine.

Abstract

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 eIF2alpha 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 D1 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.

• Authors: Carmine Stolfi, Massimiliano Sarra, Roberta Caruso, Massimo Claudio Fantini, Daniele Fina, Roberto Pellegrini, Giampiero Palmieri, Thomas T Macdonald, Francesco Pallone, Giovanni Monteleone
• Journal: Gastroenterology (Gastroenterology) Vol. 138 Issue 1 Pg. 221-30 (Jan 2010) ISSN: 1528-0012 [Electronic] United States
• PMID: 19737563 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• 2-methoxy-5-amino-N-hydroxybenzamide
• Aminosalicylic Acids
• Anticarcinogenic Agents
• Benzamides
• Carcinogens
• Ccnd1 protein, mouse
• Cyclin D1
• Mesalamine
• Dextran Sulfate
• PERK kinase
• eIF-2 Kinase
• Azoxymethane

Topics

• Aminosalicylic Acids (chemistry, pharmacology)
• Animals
• Anticarcinogenic Agents (chemistry, pharmacology)
• Azoxymethane (pharmacology)
• Benzamides (chemistry, pharmacology)
• Carcinogens (pharmacology)
• Cell Death (drug effects)
• Cell Division (drug effects)
• Colitis (drug therapy, pathology)
• Colonic Neoplasms (chemically induced, drug therapy, pathology)
• Cyclin D1 (metabolism)
• Dextran Sulfate (pharmacology)
• Endoplasmic Reticulum (drug effects)
• Flow Cytometry
• G1 Phase (drug effects)
• Gene Silencing
• HCT116 Cells
• Humans
• Mesalamine (chemistry)
• Mice
• Resting Phase, Cell Cycle (drug effects)
• Xenograft Model Antitumor Assays
• eIF-2 Kinase (genetics)