| The BH3-mimetic ABT-737 targets the apoptotic machinery in cholangiocarcinoma cell lines resulting in synergistic interactions with zoledronic acid. | |
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MedLine Citation:
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PMID: 20473610 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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PURPOSE: In TFK-1 and EGI-1 cholangiocarcinoma cell lines, zoledronic acid (ZOL) determines an S-phase block without apoptosis. Here, we investigated the occurrence of apoptosis stigmata when ZOL is associated to the BH3-mimetic ABT-737. METHODS: In EGI-1 and TFK-1 cholangiocarcinoma cell lines untreated or treated with ABT-737 alone or in combination with ZOL, the pro-survival protein's pattern (BCL-2, BCL-XL, MCL-1, HSP72, HSP27) was investigated by biochemical criteria along with the occurrence of mitochondrial damage evaluated by cytofluorimetric analysis using a cationic dye. RESULTS: ABT-737 induced growth inhibition and significantly affected the colony-forming ability of both EGI-1 and TFK-1 cells. However, activated PARP-1 or/and caspase-3 cleavage (apoptosis markers) were detected only at the highest ABT-737 concentrations used. Combined treatment showed synergistic effect by converting the predominant cytostatic effect of ZOL into a cytotoxic one as shown by striking increment of mitochondrial harmed cells along with PARP-1 activation and caspase-3 cleavage. CONCLUSION: The lack of apoptosis following ZOL treatment in these cholangiocarcinoma cell lines appears to be multifactorial and could be ascribed to the large constitutive expression of pro-survival proteins. The efficacy of ZOL treatment requires a concomitant unleashing of apoptosis using a selective BH3-mimetic as ABT-737. The rational targeting of specific components of the apoptotic pathway may appear a useful approach to improve the treatment of refractory or relapsed cholangiocarcinoma. Combined treatment could be further explored in in vivo tumor model of cholangiocarcinoma. |
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Authors:
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Antonello A Romani; Silvia Desenzani; Marina M Morganti; Maria Cristina Baroni; Angelo F Borghetti; Paolo Soliani |
Publication Detail:
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Type: Journal Article Date: 2010-05-15 |
Journal Detail:
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Title: Cancer chemotherapy and pharmacology Volume: 67 ISSN: 1432-0843 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-02-22 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: Germany |
Other Details:
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Languages: eng Pagination: 557-67 Citation Subset: IM |
Affiliation:
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Dipartimento di Scienze Chirurgiche, Sezione di Clinica Chirurgica e dei Trapianti d'Organo, Università degli Studi di Parma, Via Gramsci 14, 43100, Parma, Italy. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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