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Inhibition of Bcl-2 and Bcl-X enhances chemotherapy sensitivity in hepatoblastoma cells.
MedLine Citation:
PMID:  20680965     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
BACKGROUND: An increased expression of anti-apoptotic proteins is regularly found in malignant cells, contributing to their clonal expansion by conferring an improved survival ability. In Hepatoblastoma (HB) apoptosis regulation contributes to resistance and therapy failure, therefore we modulated apoptosis sensitivity of HB cells for an improved cytotoxic activity of commonly used drugs. PROCEDURE: Apoptosis-related proteins were quantified in HB cells (HuH6 and HepT1) using protein assays. Interaction of ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xL, and Bcl-W with cytotoxic drugs was monitored in a proliferation assay. Apoptosis induction was measured by caspase-3 activity. RESULTS: We found high levels of the anti-apoptotic protein Bcl-2 and Bcl-X as well as low levels of pro-apoptotic protein Bax and Bad in both HB cell lines. ABT-737 induced apoptosis in HuH6 and HepT1 cells at concentrations higher than 1 µM. ABT-737 also enhanced the cytotoxic effect of cisplatin (CDDP), doxorubicin (DOXO), etoposide and paclitaxel when used as combination therapy. HuH6 expressed slightly higher pro-apoptotic and lower anti-apoptotic protein levels than HepT1, which may explain the stronger enhancement of cytostatic drug effects in HuH6 cells when treated in combination with ABT-737. CONCLUSION: The observed anti-apoptotic phenotype in HB cell lines may contribute to resistance to cytotoxic drugs used in the standard treatment protocol of HB. These pre-clinical results suggest that apoptosis sensitizers with BH-3 mimicry, such as ABT-737, should be further evaluated in preclinical models of HB.
Authors:
Justus Lieber; Bettina Kirchner; Carmen Eicher; Steven W Warmann; Guido Seitz; Jörg Fuchs; Sorin Armeanu-Ebinger
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Pediatric blood & cancer     Volume:  55     ISSN:  1545-5017     ISO Abbreviation:  Pediatr Blood Cancer     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-10-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101186624     Medline TA:  Pediatr Blood Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1089-95     Citation Subset:  IM    
Affiliation:
Department of Pediatric Surgery, University Children's Hospital, Tübingen, Germany.
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