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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7352625 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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