| Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells. | |
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MedLine Citation:
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PMID: 19464430 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Antonello A Romani; Silvia Desenzani; Marina M Morganti; Silvia La Monica; Angelo F Borghetti; Paolo Soliani |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2009-04-11 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 78 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-05-25 Completed Date: 2009-06-17 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 133-41 Citation Subset: IM |
Affiliation:
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Dipartimento di Medicina Sperimentale, Sezione di Patologia Molecolare ed Immunologia, Università degli Studi di Parma, via Volturno 39, 43100 Parma, Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects,
physiology* Cell Line, Tumor Cell Proliferation / drug effects Cholangiocarcinoma / drug therapy*, pathology Diphosphonates / pharmacology, therapeutic use* Humans Imidazoles / pharmacology, therapeutic use* S Phase / drug effects, physiology* |
| Chemical | |
Reg. No./Substance:
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0/Diphosphonates; 0/Imidazoles; 118072-93-8/zoledronic acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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