TY - JOUR T1 - A method to identify physical, chemical and biological factors that trigger Bcl-xL-mediated apoptosis JF - bioRxiv DO - 10.1101/2020.01.13.904714 SP - 2020.01.13.904714 AU - Aleksandr Ianevski AU - Evgeny Kulesskiy AU - Klara Krpina AU - Guofeng Lou AU - Yahyah Aman AU - Andrii Bugai AU - Koit Aasumets AU - Yevhen Akimov AU - Daria Bulanova AU - Kiira Gildemann AU - Albert F. Arutyunyan AU - Olga Yu. Susova AU - Alexei L. Zhuze AU - Valentyn Oksenych AU - Hilde Lysvand AU - Joachim M. Gerhold AU - Magnar Bjørås AU - Pål Johansen AU - Anders Waage AU - Caroline Heckman AU - Evandro F. Fang AU - Denis E. Kainov Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/01/13/2020.01.13.904714.abstract N2 - We demonstrated recently that different viruses and transfected viral RNA or plasmid DNA killed human non-malignant cells sensitized with Bcl-xL-specific inhibitor A-1155463. Here, we show that DNA-damaging agent 4-nitroquinoline-1-oxide (4NQO) killed human non-malignant as well as malignant cells and the small roundworm C. elegans when combined with A-1155463, but not with Bcl-2- or Mcl-1-specific agents. The synergistic effect of 4NQO-A-1155463 combination was p53 dependent and was associated with the release of Bad and Bax from Bcl-xL, indicating that Bcl-xL linked DNA damage response pathways, p53 signalling and apoptosis. Other anticancer drugs (i.e. amsacrine, SN38, cisplatin, mitoxantrone, dactinomycin. dinaciclib, UCN-01, bortezomib, and S63845), as well as birth-control drug 17α-ethynylestradiol, immunosuppressant cyclosporin, antiviral agent brincidofovir, DNA binding probes MB2Py(Ac), DB2Py(4) and DBPy(5) and UV radiation also killed A-1155463-sensitized non-malignant cells. Thus, we established a method to identify physical, chemical and biological factors, which trigger Bcl-xL-mediated apoptosis. The method could be used in the development of novel anticancer therapies based on systemic Bcl-xL-specific inhibitor and local radiation, oncolytic virus infection or chemotherapy. ER -