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

1
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7028 Trondheim, Norway
2
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland
3
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway
4
Department of Biochemistry and Developmental Biology, University of Helsinki, 00014 Helsinki, Finland
5
Institute of Technology, University of Tartu, 50090 Tartu, Estonia
6
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
7
Institute of Carcinogenesis, FSBI “N.N. Blokhin National Medical Research Center of Oncology”, The Ministry of Health of the Russian Federation, 119991 Moscow, Russia
8
Department of Hematology, St. Olav’s University Hospital, 7030 Trondheim, Norway
9
Department of Dermatology, University of Zurich, 8006 Zurich, Switzerland
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1694; https://doi.org/10.3390/cancers12061694
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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