title: Comparative study of antitumor effects of bromelain and papain in human cholangiocarcinoma cell lines.
abstract: Cholangiocarcinoma (CC) worldwide is the most common biliary malignancy with poor prognostic value and new systemic treatments are desirable. Plant extracts like bromelain and papain, which are cysteine proteases from the fruit pineapple and papaya, are known to have antitumor activities. Therefore, in this study for the first time we investigated the anticancer effect of bromelain and papain in intra- and extrahepatic human CC cell lines. The effect of bromelain and papain on human CC cell growth, migration, invasion and epithelial plasticity was analyzed using cell proliferation, wound healing, invasion and apoptosis assay, as well as western blotting. Bromelain and papain lead to a decrease in the proliferation, invasion and migration of CC cells. Both plant extracts inhibited NFκB/AMPK signalling as well as their downstream signalling proteins such as p-AKT, p-ERK, p-Stat3. Additionally, MMP9 and other epithelial-mesenchymal-transition markers were partially found to be downregulated. Apoptosis was induced after bromelain and papain treatment. Interestingly, bromelain showed an overall more effective inhibition of CC as compared to papain. siRNA mediated silencing of NFκB on CC cells indicated that bromelain and papain have cytotoxic effects on human CC cell lines and bromelain and partially papain in comparison impair tumor growth by NFκB/AMPK signalling. Especially bromelain can evolve as promising, potential therapeutic option that might open new insights for the treatment of human CC.
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, D-72076 Tübingen, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Müller
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, D-72076 Tübingen, Germany.
authors.forename: Samarpita
authors.initials: S
authors.lastname: Barat
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, D-72076 Tübingen, Germany.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, D-72076 Tübingen, Germany.
authors.forename: Khac Cuong
authors.initials: KC
authors.lastname: Bui
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, D-72076 Tübingen, Germany.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bozko
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, D-72076 Tübingen, Germany.
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, D-72076 Tübingen, Germany.
authors.forename: Ruben R
authors.initials: RR
authors.lastname: Plentz
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D001963:Bromelains / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010206:Papain / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D001963:Bromelains; D055372:AMP-Activated Protein Kinases; D010206:Papain