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Autophagic flux blo...
Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib
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- Ladds, Marcus J. G. W. (författare)
- Karolinska Institutet
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- Pastor-Fernandez, Andres (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden
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- Popova, Gergana (författare)
- Karolinska Institutet
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- van Leeuwen, Ingeborg M. M. (författare)
- Karolinska Institutet
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- Eng, Kai Er (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden
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- Drummond, Catherine J. (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden
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- Johansson, Lars (författare)
- Karolinska Inst, Dept Med Biochem & Biophys, Chem Biol Consortium Sweden, Div Translat Med & Chem Biol,Sci Life Lab, Stockholm, Sweden
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- Svensson, Richard (författare)
- Uppsala universitet,Institutionen för farmaci
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- Westwood, Nicholas J. (författare)
- Univ St Andrews, Sch Chem & Biomed Sci, Res Complex, St Andrews, Fife, Scotland;EaStCHEM, Res Complex, St Andrews, Fife, Scotland
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- McCarthy, Anna R. (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden
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- Tholander, Fredrik (författare)
- Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden
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- Popa, Mihaela (författare)
- Univ Bergen, Dept Clin Sci, Bergen, Norway
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- Lane, David P. (författare)
- Karolinska Institutet
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- McCormack, Emmet (författare)
- Univ Bergen, Dept Clin Sci, Bergen, Norway;Haukeland Hosp, Dept Internal Med, Hematol Sect, Bergen, Norway
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- McInerney, Gerald M. (författare)
- Karolinska Institutet
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- Bhatia, Ravi (författare)
- Univ Alabama Birmingham, Dept Hematol & Oncol, Birmingham, AL USA
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- Lain, Sonia (författare)
- Karolinska Institutet
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(creator_code:org_t)
- 2018-04-23
- 2018
- Engelska.
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://journals.plo...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors.
Ämnesord
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
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Till lärosätets databas
- Av författaren/redakt...
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Ladds, Marcus J. ...
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Pastor-Fernandez ...
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Popova, Gergana
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van Leeuwen, Ing ...
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Eng, Kai Er
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Drummond, Cather ...
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visa fler...
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Johansson, Lars
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Svensson, Richar ...
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Westwood, Nichol ...
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McCarthy, Anna R ...
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Tholander, Fredr ...
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Popa, Mihaela
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Lane, David P.
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McCormack, Emmet
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McInerney, Geral ...
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Bhatia, Ravi
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Lain, Sonia
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visa färre...
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Uppsala universitet
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Karolinska Institutet