title: Goniothalamin prevents the development of chemically induced and spontaneous colitis in rodents and induces apoptosis in the HT-29 human colon tumor cell line.
abstract: Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects. As inflammation is a well-known tumor promoter, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on chemically induced and spontaneous colitis, as well as the cytotoxic effects of GTN on a human colon tumor cell line (HT-29). GTN treatments inhibited TNBS-induced acute and chronic colitis development in Wistar rats, reducing myeloperoxidase levels and inflammatory cells infiltration in the mucosa. In spontaneous-colitis using IL-10 deficient mice (C57BL/6 background), GTN prevented colitis development through downregulation of TNF-α, upregulation of SIRT-1 and inhibition of proliferation (PCNA index), without signs of toxicity after three months of treatment. In HT-29 cells, treatment with 10μM of GTN induced apoptosis by increasing BAX/BCL2, p-JNK1/JNK1, p-P38/P38 ratios as well as through ROS generation. Caspase 8, 9 and 3 activation also occurred, suggesting caspase-dependent apoptotic pathway, culminating in PARP-1 cleavage. Together with previous data, these results show the importance of GTN as a pro-apoptotic, preventive and therapeutic agent for IBD and highlight its potential as a chemopreventive agent for colon cancer.
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Campinas, SP, Brazil; Chemical, Biological and Agricultural Pluridisciplinary Research Center (CPQBA), University of Campinas, Campinas, SP, Brazil. Electronic address: vendramini.debora@gmail.com.
authors.forename: Débora Barbosa
authors.initials: DB
authors.lastname: Vendramini-Costa
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcaide
authors.affiliation: Department of Biochemistry, Institute of Biology, University of Campinas, Campinas, SP, Brazil.
authors.forename: Karin Juliane
authors.initials: KJ
authors.lastname: Pelizzaro-Rocha
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Talero
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Ávila-Román
authors.affiliation: Department of Plant Biology and Ecology, Faculty of Biology, University of Seville, Seville, Spain.
authors.forename: Sofia
authors.initials: S
authors.lastname: Garcia-Mauriño
authors.affiliation: Department of Organic Chemistry, Institute of Chemistry, University of Campinas, Campinas, SP, Brazil.
authors.forename: Ronaldo Aloise
authors.initials: RA
authors.lastname: Pilli
authors.affiliation: Chemical, Biological and Agricultural Pluridisciplinary Research Center (CPQBA), University of Campinas, Campinas, SP, Brazil; Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: João Ernesto
authors.initials: JE
authors.lastname: de Carvalho
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Motilva
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015536:Down-Regulation; D019073:HT29 Cells; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000096:biosynthesis; D011753:Pyrones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D056564:Sirtuin 1 / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D011753:Pyrones; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C103280:goniothalamin; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D020169:Caspases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Apoptosis; Chronic inflammation; Colitis; Goniothalamin; HT-29 cells; IL-10 deficient mice