Document Detail

Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells.
MedLine Citation:
PMID:  19238538     Owner:  NLM     Status:  MEDLINE    
Inhibition or downregulation of Bcl-2 represents a new therapeutic approach to by-pass chemoresistance in cancer cells. Therefore, we explored the potential of this approach in breast cancer cells. Cisplatin and paclitaxel induced apoptosis in a dose-dependent manner in MCF-7 (drug-sensitive) and MDA-MB-231 (drug-insensitive) cells. Furthermore, when we transiently silenced Bcl-2, both cisplatin and paclitaxel induced apoptosis more than parental cells. Dose dependent induction of apoptosis by drugs was enhanced by the pre-treatment of these cells with HA14-1, a Bcl-2 inhibitor. Although the effect of cisplatin was significant on both cell lines, the effect of paclitaxel was much less potent only in MDA-MB-231 cells. To further understand the distinct role of drugs in MDA-MB-231 cells pretreated with HA14-1, caspases and Bcl-2 family proteins were studied. The apoptotic effect of cisplatin with or without HA14-1 pre-treatment is shown to be caspase-dependent. Among pro-apoptotic Bcl-2 proteins, Bax and Puma were found to be up-regulated whereas Bcl-2 and Bcl-x(L) were down-regulated when cells were pretreated with HA14-1 followed by paclitaxel or cisplatin. Enforced Bcl-2 expression in MDA-MB-231 cells abrogated the sensitizing effect of HA14-1 in cisplatin induced apoptosis. These results suggest that the potentiating effect of HA14-1 is drug and cell type specific and may not only depend on the inhibition of Bcl-2. Importantly, alteration of other pro-apoptotic or anti-apoptotic Bcl-2 family members may dictate the apoptotic response when HA14-1 is combined with chemotherapeutic drugs.
Elif Damla Arisan; Ozgur Kutuk; Tugsan Tezil; Cagri Bodur; Dilek Telci; Huveyda Basaga
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-02-24
Journal Detail:
Title:  Breast cancer research and treatment     Volume:  119     ISSN:  1573-7217     ISO Abbreviation:  Breast Cancer Res. Treat.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-12-18     Completed Date:  2010-03-10     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8111104     Medline TA:  Breast Cancer Res Treat     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  271-81     Citation Subset:  IM    
Biological Sciences and Bioengineering Program, Faculty of Natural Sciences and Engineering, Sabanci University, Istanbul, Turkey.
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MeSH Terms
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects*
Apoptosis Regulatory Proteins / metabolism
Benzopyrans / pharmacology
Breast Neoplasms / genetics,  metabolism,  pathology*
Caspases / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Cisplatin / pharmacology
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / drug effects*
Nitriles / pharmacology
Paclitaxel / pharmacology
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*,  genetics,  metabolism
RNA Interference
Time Factors
bcl-2-Associated X Protein / metabolism
bcl-X Protein / metabolism
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/BAX protein, human; 0/BBC3 protein, human; 0/BCL2L1 protein, human; 0/Benzopyrans; 0/Nitriles; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2-Associated X Protein; 0/bcl-X Protein; 0/ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; 15663-27-1/Cisplatin; 33069-62-4/Paclitaxel; EC 3.4.22.-/Caspases

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