title: Antitumor effect of forbesione isolated fromGarcinia hanburyion cholangiocarcinomain vitroandin vivo.
abstract: Cholangiocarcinoma (CCA) is a malignancy with no effective therapy and poor prognosis. Forbesione, a caged xanthone isolated fromGarcinia hanburyi, has been reported to inhibit proliferation and to induce apoptosis in human CCA cell lines. The present study aimed to further explore the potential anticancer properties of forbesione by testing its effects against the hamster CCA cell line Ham-1in vitroandin vivo. It was observed that forbesione inhibited the growth of Ham-1 cellsin vitroand suppressed Ham-1 growth as allograft in hamsters by inducing cell cycle arrest at the S phase. This was mediated by decreasing the protein expression of cyclin E, cyclin A and cyclin-dependent kinase 2. In addition, increased expression of p21 and p27 was detected, which could possibly explain the reduced expression of proliferating cell nuclear antigen and of the bile duct cell marker cytokeratin 19 observed in forbesione-treated Ham-1 cellsin vitroand in tumor tissues of forbesione-treated hamsters. Furthermore, forbesione induced apoptosis through multiple pathways. The death receptor pathway was activated by increased expression of Fas, Fas-associated death domain and activated caspase-3, along with decreased expression of procaspase-8 and procaspase-3. The mitochondrial pathway was driven by increased expression of B-cell lymphoma (Bcl)-2-like protein 4, activated caspase-9 and inhibitor of κB-α, along with decreased expression of Bcl-2, survivin, procaspase-9 and nuclear factor-κB/p65. The endoplasmic reticulum pathway was stimulated by increased expression of activated caspase-12 and decreased expression of procaspase-12. No side effects or toxicity were observed in forbesione-treated hamsters. Thus, forbesione is a potential drug candidate for cancer therapy that deserves further investigation.
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Center of Excellence for Innovation in Chemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Parichart
authors.initials: P
authors.lastname: Boueroy
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Center of Excellence for Innovation in Chemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Chariya
authors.initials: C
authors.lastname: Hahnvajanawong
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Parasitology, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Thidarut
authors.initials: T
authors.lastname: Boonmars
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Center of Excellence for Innovation in Chemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Sunitta
authors.initials: S
authors.lastname: Saensa-Ard
authors.affiliation: Center of Excellence for Innovation in Chemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Pharmacognosy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Natthinee
authors.initials: N
authors.lastname: Anantachoke
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Biochemistry, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Kulthida
authors.initials: K
authors.lastname: Vaeteewoottacharn
authors.affiliation: Center of Excellence for Innovation in Chemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Department of Chemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Vichai
authors.initials: V
authors.lastname: Reutrakul
keywords: apoptosis; cell cycle arrest; cholangiocarcinoma; forbesione