tropisetron and Colonic-Neoplasms

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.

Topics: Animals; beta Catenin; Carcinogenesis; Colon; Colonic Neoplasms; Cyclooxygenase 2; Disease Models, Animal; Female; Humans; Indoles; Inflammatory Bowel Diseases; Interleukin-1beta; Mice; Mice, Inbred BALB C; Serotonin; Serotonin 5-HT3 Receptor Antagonists; Toll-Like Receptor 4; Tropisetron; Tumor Necrosis Factor-alpha