title: Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells.
abstract: Cholangiocarcinoma is the second most common primary hepatic neoplasia and the only curative therapy is surgical resection or liver transplantation. Biphosphonates (BPs) are an emerging class of drugs widely used to treat bone diseases and also appear to possess direct antitumor activity. In two human cholangiocarcinoma cell lines (TFK-1 and EGI-1) we investigated, for the first time, the activity of zoledronic acid by determining proliferation, cell cycle analysis and apoptosis. The results obtained indicate that zoledronic acid induces cell-narrowing and growth inhibition, both reversed by 25 microM GGOH, and significantly affects the colony-forming ability of these cells. The inhibition by zoledronic acid of Rap1A prenylation was reversed in cell co-treated with GGOH. At 10-50 microM zoledronic acid exerted an S-phase cell cycle arrest which was confirmed by changes in the level of cyclins and of regulators p27(KIP1) and pRb. Interestingly, the expression level of cyclin A (putative S-phase marker) shows a dose-dependent increment in contrast to the decrement of cyclin D1 (putative G1 phase marker). However, neither hypodiploid cells nor cleaved PARP or caspase-3 was detected. The lack of TP53 or loss of its function, the large constitutive expressions of anti-apoptotic proteins Bcl-xL and HSP27 together with the low level of the pro-apoptotic Bax are the likely factors which protect cells from apoptosis. In conclusion, our study indicates that zoledronic acid induces S-phase arrest and cell-narrowing, both reversed by GGOH and, by changing the delicate balance between pro- and anti-apoptotic proteins, allows survival of cholangiocarcinoma cells.
authors.affiliation: Dipartimento di Medicina Sperimentale, Sezione di Patologia Molecolare ed Immunologia, Università degli Studi di Parma, via Volturno 39, 43100 Parma, Italy.
authors.forename: Antonello A
authors.initials: AA
authors.lastname: Romani
authors.forename: Silvia
authors.initials: S
authors.lastname: Desenzani
authors.forename: Marina M
authors.initials: MM
authors.lastname: Morganti
authors.forename: Silvia
authors.initials: S
authors.lastname: La Monica
authors.forename: Angelo F
authors.initials: AF
authors.lastname: Borghetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Soliani
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016196:S Phase / Q000187:drug effects / Q000502:physiology*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid