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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

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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.

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Acknowledgement

This work was supported by grants from the Agency for Science, Technology and Research (A*STAR), Singapore.

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  1. Anthony E. Ting

    Present address: Athersys Inc., Cleveland, Ohio, USA

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  1. Institute of Molecular and Cell Biology, 30 Medical Drive, 117609, Singapore, Republic of Singapore

    Yee-Joo Tan, Eileen Teng & Anthony E. Ting

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Correspondence to Yee-Joo Tan.

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Tan, YJ., Teng, E. & Ting, A.E. 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. J Cancer Res Clin Oncol 129, 437–448 (2003). https://doi.org/10.1007/s00432-003-0464-4

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