title: The tumor-selective viral protein apoptin effectively kills human biliary tract cancer cells.
abstract: Biliary tract cancer, or cholangiocarcinoma, has a poor prognosis. Resection is the only curative treatment, but only a minority of patients are eligible. Chemotherapy and gamma-irradiation are merely palliative, as they are unable to remove the malignancy completely. The chicken anemia virus-derived protein apoptin induces apoptosis in a wide range of human tumor cells and is not hindered by mutations inactivating p53 or by overexpression of Bcl-2, changes known to frustrate chemotherapy and radiation therapy. We examined whether apoptin kills human biliary tract cancer cells. Expression of apoptin by means of plasmids caused extensive cell death in three independent cholangiocarcinoma cell lines, CC-LP, CC-SW, and Mz-ChA-1, regardless of their oncogenic mutations, which included inactivated p16 and p53 and the disruption of the transforming growth factor beta signaling pathway. In vitro delivery of apoptin by an adenoviral vector completely eradicated cholangiocarcinoma cells. Moreover, coexpression of the broad-spectrum caspase inhibitor p35 with apoptin only delayed the induced cell death. Changes in nuclear morphology still occurred early after transfection, and nuclei eventually disintegrated, suggesting that apoptin-induced cell death in these cells is not blocked by mutations in either the initiation or execution phase of apoptosis. The efficient induction of cell death by apoptin in cholangiocarcinoma cell lines makes apoptin an attractive candidate for molecular therapy of biliary tract cancer.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9503, 2300 RA Leiden, The Netherlands.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Pietersen
authors.forename: Saskia A
authors.initials: SA
authors.lastname: Rutjes
authors.forename: Joost
authors.initials: J
authors.lastname: van Tongeren
authors.forename: Ronald
authors.initials: R
authors.lastname: Vogels
authors.forename: John G
authors.initials: JG
authors.lastname: Wesseling
authors.forename: Mathieu H M
authors.initials: MH
authors.lastname: Noteborn
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D001661:Biliary Tract Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D061945:Caspase Inhibitors; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D017727:Chicken anemia virus / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D005822:Genetic Vectors; D006801:Humans; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D036022:Capsid Proteins; D061945:Caspase Inhibitors; D016159:Tumor Suppressor Protein p53; C091717:VP3 protein, Chicken anemia virus; D014764:Viral Proteins; C081618:p35 protein, Nucleopolyhedrovirus