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E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines

The CDK/Rb/E2F pathway is commonly disrupted in lung cancer, and thus, it is predicted that blocking the E2F pathway would have therapeutic potential. To test this hypothesis, we have examined the activity of HLM006474 (a small molecule pan-E2F inhibitor) in lung cancer cell lines as a single agent...

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Detalles Bibliográficos
Autores principales: Kurtyka, Courtney A., Chen, Lu, Cress, W. Douglas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022639/
https://www.ncbi.nlm.nih.gov/pubmed/24831239
http://dx.doi.org/10.1371/journal.pone.0096357
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author Kurtyka, Courtney A.
Chen, Lu
Cress, W. Douglas
author_facet Kurtyka, Courtney A.
Chen, Lu
Cress, W. Douglas
author_sort Kurtyka, Courtney A.
collection PubMed
description The CDK/Rb/E2F pathway is commonly disrupted in lung cancer, and thus, it is predicted that blocking the E2F pathway would have therapeutic potential. To test this hypothesis, we have examined the activity of HLM006474 (a small molecule pan-E2F inhibitor) in lung cancer cell lines as a single agent and in combination with other compounds. HLM006474 reduces the viability of both SCLC and NSCLC lines with a biological IC(50) that varies between 15 and 75 µM, but with no significant difference between the groups. Combination of HLM006474 with cisplatin and gemcitabine demonstrate little synergy; however, HLM006474 synergizes with paclitaxel. Surprisingly, we discovered that brief treatment of cells with HLM006474 led to an increase of E2F3 protein levels (due to de-repression of these promoter sites). Since paclitaxel sensitivity has been shown to correlate with E2F3 levels, we hypothesized that HLM006474 synergy with paclitaxel may be mediated by transient induction of E2F3. To test this, H1299 cells were depleted of E2F3a and E2F3b with siRNA and treated with paclitaxel. Assays of proliferation showed that both siRNAs significantly reduced paclitaxel sensitivity, as expected. Taken together, these results suggest that HLM006474 may have efficacy in lung cancer and may be useful in combination with taxanes.
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spelling pubmed-40226392014-05-21 E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines Kurtyka, Courtney A. Chen, Lu Cress, W. Douglas PLoS One Research Article The CDK/Rb/E2F pathway is commonly disrupted in lung cancer, and thus, it is predicted that blocking the E2F pathway would have therapeutic potential. To test this hypothesis, we have examined the activity of HLM006474 (a small molecule pan-E2F inhibitor) in lung cancer cell lines as a single agent and in combination with other compounds. HLM006474 reduces the viability of both SCLC and NSCLC lines with a biological IC(50) that varies between 15 and 75 µM, but with no significant difference between the groups. Combination of HLM006474 with cisplatin and gemcitabine demonstrate little synergy; however, HLM006474 synergizes with paclitaxel. Surprisingly, we discovered that brief treatment of cells with HLM006474 led to an increase of E2F3 protein levels (due to de-repression of these promoter sites). Since paclitaxel sensitivity has been shown to correlate with E2F3 levels, we hypothesized that HLM006474 synergy with paclitaxel may be mediated by transient induction of E2F3. To test this, H1299 cells were depleted of E2F3a and E2F3b with siRNA and treated with paclitaxel. Assays of proliferation showed that both siRNAs significantly reduced paclitaxel sensitivity, as expected. Taken together, these results suggest that HLM006474 may have efficacy in lung cancer and may be useful in combination with taxanes. Public Library of Science 2014-05-15 /pmc/articles/PMC4022639/ /pubmed/24831239 http://dx.doi.org/10.1371/journal.pone.0096357 Text en © 2014 Kurtyka et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kurtyka, Courtney A.
Chen, Lu
Cress, W. Douglas
E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines
title E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines
title_full E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines
title_fullStr E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines
title_full_unstemmed E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines
title_short E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines
title_sort e2f inhibition synergizes with paclitaxel in lung cancer cell lines
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022639/
https://www.ncbi.nlm.nih.gov/pubmed/24831239
http://dx.doi.org/10.1371/journal.pone.0096357
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