Isolation of a novel thioflavin S-derived compound that inhibits BAG-1-mediated protein interactions and targets BRAF inhibitor-resistant cell lines.
| Autor: | Enthammer M; Corresponding Author: Jakob Troppmair, Innsbruck Medical University, Innrain 66, Innsbruck 6020, Austria. Jakob.troppmair@i-med.ac.at., Papadakis ES, Salomé Gachet M, Deutsch M, Schwaiger S, Koziel K, Ashraf MI, Khalid S, Wolber G, Packham G, Cutress RI, Stuppner H, Troppmair J |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Molecular cancer therapeutics [Mol Cancer Ther] 2013 Nov; Vol. 12 (11), pp. 2400-14. Date of Electronic Publication: 2013 Sep 18. |
| DOI: | 10.1158/1535-7163.MCT-13-0142 |
| Abstrakt: | Protein-protein interactions mediated through the C-terminal Bcl-2-associated athanogene (BAG) domain of BAG-1 are critical for cell survival and proliferation. Thioflavin S (NSC71948)-a mixture of compounds resulting from the methylation and sulfonation of primulin base-has been shown to dose-dependently inhibit the interaction between BAG-1 and Hsc70 in vitro. In human breast cancer cell lines, with high BAG-1 expression levels, Thioflavin S reduces the binding of BAG-1 to Hsc70, Hsp70, or CRAF and decreases proliferation and viability. Here, we report the development of a protocol for the purification and isolation of biologically active constituents of Thioflavin S and the characterization of the novel compound Thio-2. Thio-2 blocked the growth of several transformed cell lines, but had much weaker effects on untransformed cells. Thio-2 also inhibited the proliferation of melanoma cell lines that had become resistant to treatment with PLX4032, an inhibitor of mutant BRAF. In transformed cells, Thio-2 interfered with intracellular signaling at the level of RAF, but had no effect on the activation of AKT. Thio-2 decreased binding of BAG-1 to Hsc70 and to a lesser extent BRAF in vitro and in vivo, suggesting a possible mechanism of action. Given that tumors frequently develop resistance to kinase inhibitors during treatment, Thio-2 and related compounds may offer promising alternative strategies to currently available therapies. (©2013 AACR.) |
| Databáze: | MEDLINE |
| Externí odkaz: |
|