Chemical, physical and biological factors triggering Bcl-xL-mediated apoptosis

We demonstrated recently that Bcl-xL-specific inhibitors prematurely killed virus-infected or RNA/DNA-transfected cells. Here we showed that Bcl-xL-specific agent A-1155463 prematurely killed human non-malignant as well as malignant cells and the small roundworm C. elegans when combined with DNA-damaging agent 4-nitroquinoline-1-oxide (4NQO). The synergistic effect of 4NQO-A-1155463 combination was p53-dependent, was associated with the release of Bad and Bax from Bcl-xL and with mitochondrial outer membrane permeabilization (MOMP), indicating that Bcl-xL linked DNA damage response, p53 signalling and apoptotic pathways. In addition, combinations of Bcl-xL specific inhibitors with several anticancer agents, immunosuppressant drug, antiviral drug, DNA binding probes or UV radiation also killed cells. Thus, we identified biological, chemical and physical factors triggering Bcl-xL-mediated apoptosis.