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Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells

Selective inhibitors of nuclear export (SINE) are small molecules in development as anti-cancer agents. The first-in-class SINE, selinexor, is in clinical trials for blood and solid cancers. Selinexor forms a covalent bond with exportin-1 at cysteine-528, and blocks its ability to export cargos. Pre...

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Autores principales: Burke, Russell T., Marcus, Joshua M., Orth, James D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503625/
https://www.ncbi.nlm.nih.gov/pubmed/28467801
http://dx.doi.org/10.18632/oncotarget.17063
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author Burke, Russell T.
Marcus, Joshua M.
Orth, James D.
author_facet Burke, Russell T.
Marcus, Joshua M.
Orth, James D.
author_sort Burke, Russell T.
collection PubMed
description Selective inhibitors of nuclear export (SINE) are small molecules in development as anti-cancer agents. The first-in-class SINE, selinexor, is in clinical trials for blood and solid cancers. Selinexor forms a covalent bond with exportin-1 at cysteine-528, and blocks its ability to export cargos. Previous work has shown strong cell cycle effects and drug-induced cell death across many different cancer-derived cell lines. Here, we report strong cell cycle-associated DNA double-stranded break formation upon the treatment of cancer cells with SINE. In multiple cell models, selinexor treatment results in the formation of clustered DNA damage foci in 30-40% of cells within 8 hours that is dependent upon cysteine-528. DNA damage strongly correlates with G1/S-phase and decreased DNA replication. Live cell microscopy reveals an association between DNA damage and cell fate. Cells that form damage in G1-phase more often die or arrest, while those damaged in S/G2-phase frequently progress to cell division. Up to half of all treated cells form damage foci, and most cells that die after being damaged, were damaged in G1-phase. By comparison, non-transformed cell lines show strong cell cycle effects but little DNA damage and less death than cancer cells. Significant drug combination effects occur when selinexor is paired with different classes of agents that either cause DNA damage or that diminish DNA damage repair. These data present a novel effect of exportin-1 inhibition and provide a strong rationale for multiple combination treatments of selinexor with agents that are currently in use for the treatment of different solid cancers.
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spelling pubmed-55036252017-07-11 Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells Burke, Russell T. Marcus, Joshua M. Orth, James D. Oncotarget Research Paper Selective inhibitors of nuclear export (SINE) are small molecules in development as anti-cancer agents. The first-in-class SINE, selinexor, is in clinical trials for blood and solid cancers. Selinexor forms a covalent bond with exportin-1 at cysteine-528, and blocks its ability to export cargos. Previous work has shown strong cell cycle effects and drug-induced cell death across many different cancer-derived cell lines. Here, we report strong cell cycle-associated DNA double-stranded break formation upon the treatment of cancer cells with SINE. In multiple cell models, selinexor treatment results in the formation of clustered DNA damage foci in 30-40% of cells within 8 hours that is dependent upon cysteine-528. DNA damage strongly correlates with G1/S-phase and decreased DNA replication. Live cell microscopy reveals an association between DNA damage and cell fate. Cells that form damage in G1-phase more often die or arrest, while those damaged in S/G2-phase frequently progress to cell division. Up to half of all treated cells form damage foci, and most cells that die after being damaged, were damaged in G1-phase. By comparison, non-transformed cell lines show strong cell cycle effects but little DNA damage and less death than cancer cells. Significant drug combination effects occur when selinexor is paired with different classes of agents that either cause DNA damage or that diminish DNA damage repair. These data present a novel effect of exportin-1 inhibition and provide a strong rationale for multiple combination treatments of selinexor with agents that are currently in use for the treatment of different solid cancers. Impact Journals LLC 2017-04-12 /pmc/articles/PMC5503625/ /pubmed/28467801 http://dx.doi.org/10.18632/oncotarget.17063 Text en Copyright: © 2017 Burke et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Burke, Russell T.
Marcus, Joshua M.
Orth, James D.
Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells
title Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells
title_full Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells
title_fullStr Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells
title_full_unstemmed Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells
title_short Inhibition of exportin-1 function results in rapid cell cycle-associated DNA damage in cancer cells
title_sort inhibition of exportin-1 function results in rapid cell cycle-associated dna damage in cancer cells
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503625/
https://www.ncbi.nlm.nih.gov/pubmed/28467801
http://dx.doi.org/10.18632/oncotarget.17063
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