Tropisetron suppresses colitis-associated cancer in a mouse model in the remission stage.
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.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Hossein
H
Amini-Khoei
Department of Molecular Pathology, University of Queensland, UQ Center for Clinical Research, Queensland, Australia.
Majid
M
Momeny
Department of Pathology, Imam Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
Alireza
A
Abdollahi
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Ahmad Reza
AR
Dehpour
Department of Biochemistry and Medical Genetics, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
Shayan
S
Amiri
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Arya
A
Haj-Mirzaian
Department of Pathology, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Seyed Mohammad
SM
Tavangar
Hematology/Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Seyed Hamid
SH
Ghaffari
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: rahimian78@gmail.com.
Reza
R
Rahimian
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: ejtemam@gmail.com.
Shahram Ejtemaei
SE
Mehr
D000818:Animals; D063646:Carcinogenesis; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012701:Serotonin / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D000077526:Tropisetron; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C587672:IL1B protein, mouse; D007211:Indoles; D053583:Interleukin-1beta; D058831:Serotonin 5-HT3 Receptor Antagonists; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D012701:Serotonin; D000077526:Tropisetron; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
5-HT3 receptor; CAC; Colitis; Serotonin