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Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis

Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7028 Trondheim, Norway
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway
Department of Biochemistry and Developmental Biology, University of Helsinki, 00014 Helsinki, Finland
Institute of Technology, University of Tartu, 50090 Tartu, Estonia
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
Institute of Carcinogenesis, FSBI “N.N. Blokhin National Medical Research Center of Oncology”, The Ministry of Health of the Russian Federation, 119991 Moscow, Russia
Department of Hematology, St. Olav’s University Hospital, 7030 Trondheim, Norway
Department of Dermatology, University of Zurich, 8006 Zurich, Switzerland
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1694;
Received: 11 June 2020 / Revised: 23 June 2020 / Accepted: 24 June 2020 / Published: 25 June 2020
Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development. View Full-Text
Keywords: apoptosis; Bcl-xL; oncolytics; navitoclax apoptosis; Bcl-xL; oncolytics; navitoclax
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Ianevski, A.; Kulesskiy, E.; Krpina, K.; Lou, G.; Aman, Y.; Bugai, A.; Aasumets, K.; Akimov, Y.; Bulanova, D.; Gildemann, K.; Arutyunyan, A.F.; Susova, O.Y.; Zhuze, A.L.; Ji, P.; Wang, W.; Holien, T.; Bugge, M.; Zusinaite, E.; Oksenych, V.; Lysvand, H.; Gerhold, J.M.; Bjørås, M.; Johansen, P.; Waage, A.; Heckman, C.A.; Fang, E.F.; Kainov, D.E. Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis. Cancers 2020, 12, 1694.

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