Tropisetron suppresses colitis-associated cancer in a mouse model in the remission stage.

Abstract

Patients with inflammatory bowel disease (IBD) have a high risk for development of colitis-associated cancer (CAC). Serotonin is a neurotransmitter produced by enterochromaffin cells of the intestine. Serotonin and its receptors, mainly 5-HT3 receptor, are overexpressed in IBD and promote development of CAC through production of inflammatory cytokines. In the present study, we demonstrated the in vivo activity of tropisetron, a 5-HT3 receptor antagonist, against experimental CAC. CAC was induced by azoxymethane (AOM)/dextran sodium sulfate (DDS) in BALB/c mice. The histopathology of colon tissue was performed. Beta-catenin and Cox-2 expression was evaluated by immunohistochemistry as well as quantitative reverse transcription-PCR (qRT-PCR). Alterations in the expression of 5-HT3 receptor and inflammatory-associated genes such as Il-1β, Tnf-α, Tlr4 and Myd88 were determined by qRT-PCR. Our results showed that tumor development in tropisetron-treated CAC group was significantly lower than the controls. The qRT-PCR analysis demonstrated that the expression of 5-HT3 receptor was significantly increased following CAC induction. In addition, tropisetron reduced expression of β-catenin and Cox-2 in the CAC experimental group. The levels of Il-1β, Tnf-α, Tlr4 and Myd88 were significantly decreased upon tropisetron treatment in the AOM/DSS group. Taken together, our data show that tropisetron inhibits development of CAC probably by attenuation of inflammatory reactions in the colitis.

• Authors: Hossein Amini-Khoei, Majid Momeny, Alireza Abdollahi, Ahmad Reza Dehpour, Shayan Amiri, Arya Haj-Mirzaian, Seyed Mohammad Tavangar, Seyed Hamid Ghaffari, Reza Rahimian, Shahram Ejtemaei Mehr
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 36 Pg. 9-16 (Jul 2016) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 27104313 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• IL1B protein, mouse
• Indoles
• Interleukin-1beta
• Serotonin 5-HT3 Receptor Antagonists
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• beta Catenin
• Serotonin
• Tropisetron
• Ptgs2 protein, mouse
• Cyclooxygenase 2

Topics

• Animals
• Carcinogenesis
• Colon (drug effects, pathology)
• Colonic Neoplasms (drug therapy, pathology)
• Cyclooxygenase 2 (genetics, metabolism)
• Disease Models, Animal
• Female
• Humans
• Indoles (therapeutic use)
• Inflammatory Bowel Diseases (drug therapy, pathology)
• Interleukin-1beta (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Serotonin (metabolism)
• Serotonin 5-HT3 Receptor Antagonists (therapeutic use)
• Toll-Like Receptor 4 (genetics, metabolism)
• Tropisetron
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• beta Catenin (genetics, metabolism)