Abstract
3512
One mechanism by which tumors either die or survive is thought to depend at least in part on the interaction between prosurvival (i.e. Bcl-2, Bcl-XL) and proapoptotic (i.e. Bax, Bak) proteins. The BH3 domain is the α-helical region of the pro-apoptotic proteins that binds to the prosurvival proteins. We have designed BH3 α-helical mimics with the ultimate goal of displacing Bcl2- and Bcl-XL-bound proapoptotic proteins and inducing tumor cell death. One of these, BH3M-6 is a non-peptide terphenyl that spacially projects side chains in a similar manner to that of the three turns of the BH3 α-helix of Bax. Using fluorescence polarization and GST-pulldown assays we showed that BH3M-6 disrupted the association of Bcl-XL with Bak and Bax, respectively. Furthermore, in intact human lung cancer A-549 cells, BH3M-6 inhibited proliferation and tumor cell survival as meeasured by MTT, soft agar and trypan blue assays. Finally, BH3M-6 induced apoptosis as demonstrated by DAPI staining, Tunel, cytochrome c release, caspase 3 activation and PARP-cleavage assays. Taken together these results show that small, non-peptidic synthetic mimics of the α-helical BH3 domain are able to inhibit the association of Bcl-XL with Bak and Bax and induce apoptosis in human cancer cells.
- American Association for Cancer Research
Volume 65, Issue 9 Supplement
