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The BH3-mimetic ABT-737 targets the apoptotic machinery in cholangiocarcinoma cell lines resulting in synergistic interactions with zoledronic acid.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2011 Mar; Vol. 67 (3), pp. 557-67. Date of Electronic Publication: 2010 May 15. - Publication Year :
- 2011
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Abstract
- 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.<br />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.<br />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.<br />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.
- Subjects :
- Antineoplastic Agents pharmacology
Apoptosis drug effects
Bile Duct Neoplasms drug therapy
Bile Duct Neoplasms pathology
Bile Ducts, Intrahepatic drug effects
Bile Ducts, Intrahepatic pathology
Cell Line, Tumor
Cholangiocarcinoma pathology
Drug Synergism
Gene Expression Regulation
Humans
Piperazines pharmacology
S Phase drug effects
Zoledronic Acid
Biphenyl Compounds pharmacology
Cholangiocarcinoma drug therapy
Diphosphonates pharmacology
Drug Delivery Systems
Imidazoles pharmacology
Nitrophenols pharmacology
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 67
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 20473610
- Full Text :
- https://doi.org/10.1007/s00280-010-1345-6