Original Article
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Nov 28, 2011; 17(44): 4858-4866
Published online Nov 28, 2011. doi: 10.3748/wjg.v17.i44.4858
Erlotinib inhibits progression to dysplasia in a colitis-associated colon cancer model
Beatriz Pagán, Angel A Isidro, Myrella L Cruz, Yuan Ren, Domenico Coppola, Jie Wu, Caroline B Appleyard
Beatriz Pagán, Angel A Isidro, Myrella L Cruz, Caroline B Appleyard, Department of Physiology and Pharmacology, Ponce School of Medicine, Ponce, PR 00732, United States
Yuan Ren, Jie Wu, Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, United States
Domenico Coppola, Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, United States
Author contributions: Appleyard CB, Wu J and Pagán B designed the research; Pagán B, Cruz ML and Ren Y performed the research; Pagán B, Isidro AA, Cruz ML, Coppola D, Appleyard CB and Wu J analyzed the data; Pagán B, Appleyard CB and Wu J wrote the paper.
Supported by National Institutes of Health Grants, No. U56 CA126379 (to Isidro AA and Appleyard CB), No. CA118809 (to Wu J); and a National Institutes of Health Predoctoral Fellowship No. F31 GM078951 (to Pagán B)
Correspondence to: Caroline B Appleyard, PhD, Professor, Department of Physiology and Pharmacology, Ponce School of Medicine, PO Box 7004, Ponce, PR 00732, United States.cappleyard@psm.edu
Telephone: +1-787-8402575 Fax: +1-787-8411040
Received: June 8, 2011
Revised: August 21, 2011
Accepted: October 14, 2011
Published online: November 28, 2011

AIM: To investigate the role of epidermal growth factor receptor (EGFR) in colitis-associated dysplasia using the EGFR tyrosine kinase inhibitor erlotinib.

METHODS: Sprague-Dawley rats received trinitrobenzene sulfonic acid (TNBS; 30 mg in 50% ethanol, ic), followed 6 wk later by reactivation with TNBS (5 mg/kg, iv) for 3 d. To induce colitis-associated dysplasia, rats then received TNBS (iv) twice a week for 10 wk. One group received erlotinib (10 mg/kg, ip) for 1 wk before the start of the reactivation of the colitis and 2 wk after (21 d); the rest received the vehicle. After rats were euthanized, the colons were removed and analyzed for damage and expression of the EGFR downstream effectors Erk1/2 and c-Myc.

RESULTS: Ninety percent of the vehicle-treated animals had dysplasia in any region of the colon. Erlotinib-treated animals had a significant decrease in the incidence of dysplasia compared to vehicle-treated animals in all regions of the colon (50.00% ± 11.47% vs 90.00% ± 10.00% in proximal, P < 0.05; 15.00% ± 8.19% vs 50.00% ± 16.67% in mid, P < 0.05; and 20.00% ± 9.17% vs 70.00% ± 15.28% in distal, P < 0.01). Erlotinib-treated animals also had reduced cell proliferation, reduced active Erk1/2, and reduced c-Myc in colon epithelium compared with the vehicle-treated animals. In vitro, erlotinib treatment was shown to markedly decrease c-Myc and pErk1/2 levels in rat epithelial cells. Proliferation of rat epithelial cells was stimulated by epidermal growth factor and inhibited by erlotinib (P < 0.05).

CONCLUSION: Erlotinib can decrease the development of colitis-associated dysplasia, suggesting a potential therapeutic use for erlotinib in patients with long-standing colitis.

Keywords: Animal model, Epidermal growth factor receptor, Colitis, Dysplasia, Erlotinib