Erschienen in:
01.08.2003 | Original Paper
A small inhibitor of the interaction between Bax and Bcl-XL can synergize with methylprednisolone to induce apoptosis in Bcl-XL-overexpressing breast-cancer cells
verfasst von:
Yee-Joo Tan, Eileen Teng, Anthony E. Ting
Erschienen in:
Journal of Cancer Research and Clinical Oncology
|
Ausgabe 8/2003
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Abstract
Purpose
To identify inhibitors of the interaction between Bax and Bcl-XL.
Methods
Using an assay based on biosensor technology, we screened a chemical library of 10,000 compounds for inhibitors of the interaction between Bax and Bcl-XL. Using cell-culture systems we tested active compounds for their ability to induce apoptosis in Bcl-XL-overexpressing MCF7 cells and increase the sensitivities of the cells to apoptosis-inducing drugs [vincristine sulphate, dexamethasone, cycloheximide and 6α-methylprednisolone (MP)].
Results
A single compound, 2′,4′,5′,7′-tetrabromofluorescein (A5), from the library was found to inhibit this interaction efficiently. Several structural analogues of A5 were tested and two of these [4′,5′-dibromofluorescein (A9) and 3,4,5,6-tetrabromofluorescein (A11)] were found to be active, and their activities were confirmed by an independent in vitro pull-down assay. These active compounds were observed to induce apoptosis in Bcl-XL-overexpressing MCF7 cells. Moreover, two of the compounds (A5 and A11) appeared to increase the sensitivities of the cells to MP. A more rigorous test using the isobologram technique showed that there is a synergistic cytotoxic effect between A11 and MP.
Conclusions
We have identified a small inhibitor of the interaction between Bax and Bcl-XL that can synergize with methylprednisolone to induce apoptosis in Bcl-XL-overexpressing breast-cancer cells.