title: Curcumin decreases cholangiocarcinogenesis in hamsters by suppressing inflammation-mediated molecular events related to multistep carcinogenesis.
abstract: Cholangiocarcinoma (CCA) is a highly metastatic tumor linked to liver fluke infection and consumption of nitrosamine-contaminated foods and is a major health problem especially in South-Eastern Asia. In search for a suitable chemopreventive agents, we investigated the effect of curcumin, a traditional anti-inflammatory agent derived from turmeric (Curcuma longa), on CCA development in an animal model by infection with the liver fluke Opisthorchis viverrini and administration of N-nitrosodimethylamine and fed with curcumin-supplemented diet. The effect of curcumin-supplemented diet on histopathological changes and survival were assessed in relation to NF-κB activation, and the expression of NF-κB-related gene products involved in inflammation, DNA damage, apoptosis, cell proliferation, angiogenesis and metastasis. Our results showed that dietary administration of this nutraceutical significantly reduced the incidence of CCA and increased the survival of animals. This correlated with the suppression of the activation of transcription factors including NF-κB, AP-1 and STAT-3, and reduction in the expression of proinflammatory proteins such as COX-2 and iNOS. The formation of iNOS-dependent DNA lesions (8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine) was inhibited. Curcumin suppressed the expression of proteins related to cell survival (bcl-2 and bcl-xL), proliferation (cyclin D1 and c-myc), tumor invasion (MMP-9 and ICAM-1) and angiogenesis (VEGF), and microvessel density. Induction of apoptotic events as indicated by caspase activation and PARP cleavage was also noted. Our results suggest that curcumin exhibits an anticarcinogenic potential via suppression of various events involved in multiple steps of carcinogenesis, which is accounted for by its ability to suppress proinflammatory pathways.
authors.affiliation: Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Suksanti
authors.initials: S
authors.lastname: Prakobwong
authors.forename: Jarinya
authors.initials: J
authors.lastname: Khoontawad
authors.forename: Puangrat
authors.initials: P
authors.lastname: Yongvanit
authors.forename: Chawalit
authors.initials: C
authors.lastname: Pairojkul
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.forename: Paiboon
authors.initials: P
authors.lastname: Sithithaworn
authors.forename: Porntip
authors.initials: P
authors.lastname: Pinlaor
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
authors.forename: Somchai
authors.initials: S
authors.lastname: Pinlaor
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018281:Cholangiocarcinoma / Q000098:blood supply / Q000517:prevention & control*; D006224:Cricetinae; D003474:Curcumin / Q000494:pharmacology*; D003854:Deoxyribonucleotides; D004032:Diet; D024202:Electrophoretic Mobility Shift Assay; D007150:Immunohistochemistry; D007249:Inflammation / Q000517:prevention & control*; D008297:Male; D008647:Mesocricetus; D016328:NF-kappa B / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D003854:Deoxyribonucleotides; D016328:NF-kappa B; D003474:Curcumin