title: Erlotinib inhibits progression to dysplasia in a colitis-associated colon cancer model.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  Erlotinib can decrease the development of colitis-associated dysplasia, suggesting a potential therapeutic use for erlotinib in patients with long-standing colitis.
authors.affiliation: Department of Physiology and Pharmacology, Ponce School of Medicine, Ponce, PR 00732, United States.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pagán
authors.forename: Angel A
authors.initials: AA
authors.lastname: Isidro
authors.forename: Myrella L
authors.initials: ML
authors.lastname: Cruz
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ren
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Appleyard
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology*; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D014302:Trinitrobenzenesulfonic Acid; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases