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

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 c...

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Autores principales: Ianevski, Aleksandr, Kulesskiy, Evgeny, Krpina, Klara, Lou, Guofeng, Aman, Yahyah, Bugai, Andrii, Aasumets, Koit, Akimov, Yevhen, Bulanova, Daria, Gildemann, Kiira, Arutyunyan, Albert F., Susova, Olga Yu., Zhuze, Alexei L., Ji, Ping, Wang, Wei, Holien, Toril, Bugge, Marit, Zusinaite, Eva, Oksenych, Valentyn, Lysvand, Hilde, Gerhold, Joachim M., Bjørås, Magnar, Johansen, Pål, Waage, Anders, Heckman, Caroline A., Fang, Evandro F., Kainov, Denis E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352625/
https://www.ncbi.nlm.nih.gov/pubmed/32630560
http://dx.doi.org/10.3390/cancers12061694
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author Ianevski, Aleksandr
Kulesskiy, Evgeny
Krpina, Klara
Lou, Guofeng
Aman, Yahyah
Bugai, Andrii
Aasumets, Koit
Akimov, Yevhen
Bulanova, Daria
Gildemann, Kiira
Arutyunyan, Albert F.
Susova, Olga Yu.
Zhuze, Alexei L.
Ji, Ping
Wang, Wei
Holien, Toril
Bugge, Marit
Zusinaite, Eva
Oksenych, Valentyn
Lysvand, Hilde
Gerhold, Joachim M.
Bjørås, Magnar
Johansen, Pål
Waage, Anders
Heckman, Caroline A.
Fang, Evandro F.
Kainov, Denis E.
author_facet Ianevski, Aleksandr
Kulesskiy, Evgeny
Krpina, Klara
Lou, Guofeng
Aman, Yahyah
Bugai, Andrii
Aasumets, Koit
Akimov, Yevhen
Bulanova, Daria
Gildemann, Kiira
Arutyunyan, Albert F.
Susova, Olga Yu.
Zhuze, Alexei L.
Ji, Ping
Wang, Wei
Holien, Toril
Bugge, Marit
Zusinaite, Eva
Oksenych, Valentyn
Lysvand, Hilde
Gerhold, Joachim M.
Bjørås, Magnar
Johansen, Pål
Waage, Anders
Heckman, Caroline A.
Fang, Evandro F.
Kainov, Denis E.
author_sort Ianevski, Aleksandr
collection PubMed
description 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.
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spelling pubmed-73526252020-07-21 Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis Ianevski, Aleksandr Kulesskiy, Evgeny Krpina, Klara Lou, Guofeng Aman, Yahyah Bugai, Andrii Aasumets, Koit Akimov, Yevhen Bulanova, Daria Gildemann, Kiira Arutyunyan, Albert F. Susova, Olga Yu. Zhuze, Alexei L. Ji, Ping Wang, Wei Holien, Toril Bugge, Marit Zusinaite, Eva Oksenych, Valentyn Lysvand, Hilde Gerhold, Joachim M. Bjørås, Magnar Johansen, Pål Waage, Anders Heckman, Caroline A. Fang, Evandro F. Kainov, Denis E. Cancers (Basel) Article 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. MDPI 2020-06-25 /pmc/articles/PMC7352625/ /pubmed/32630560 http://dx.doi.org/10.3390/cancers12061694 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ianevski, Aleksandr
Kulesskiy, Evgeny
Krpina, Klara
Lou, Guofeng
Aman, Yahyah
Bugai, Andrii
Aasumets, Koit
Akimov, Yevhen
Bulanova, Daria
Gildemann, Kiira
Arutyunyan, Albert F.
Susova, Olga Yu.
Zhuze, Alexei L.
Ji, Ping
Wang, Wei
Holien, Toril
Bugge, Marit
Zusinaite, Eva
Oksenych, Valentyn
Lysvand, Hilde
Gerhold, Joachim M.
Bjørås, Magnar
Johansen, Pål
Waage, Anders
Heckman, Caroline A.
Fang, Evandro F.
Kainov, Denis E.
Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis
title Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis
title_full Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis
title_fullStr Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis
title_full_unstemmed Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis
title_short Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis
title_sort chemical, physical and biological triggers of evolutionary conserved bcl-xl-mediated apoptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352625/
https://www.ncbi.nlm.nih.gov/pubmed/32630560
http://dx.doi.org/10.3390/cancers12061694
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