Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been proven to efficiently inhibit the proliferation of a subset of non small-cell lung cancers (NSCLC). Unfortunately, the majority of NSCLC expressing wild type EGFR is primarily resistant to EGFR-TKI...

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Autores principales:	Anke Bill, Anton Schmitz, Katharina König, Lukas C Heukamp, Jeffrey S Hannam, Michael Famulok
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/abcd96ca8a6243b0bebc9a26e3465d5a
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spelling	oai:doaj.org-article:abcd96ca8a6243b0bebc9a26e3465d5a2021-11-18T07:11:58ZAnti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.1932-620310.1371/journal.pone.0041179https://doaj.org/article/abcd96ca8a6243b0bebc9a26e3465d5a2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22815959/?tool=EBIhttps://doaj.org/toc/1932-6203Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been proven to efficiently inhibit the proliferation of a subset of non small-cell lung cancers (NSCLC). Unfortunately, the majority of NSCLC expressing wild type EGFR is primarily resistant to EGFR-TKI treatment. Here, we show that the proliferation of the gefitinib-resistant NSCLC cell lines H460 and A549 is reduced by the small molecule SecinH3 which indirectly attenuates EGFR activation by inhibition of cytohesins, a class of recently discovered cytoplasmic EGFR activators. SecinH3 and gefitinib showed a synergistic antiproliferative effect, which correlated with a profound inhibition of Akt activation and survivin expression. Treating mice bearing H460 xenografts with SecinH3 showed the antiproliferative and pro-apoptotic effect of SecinH3 in vivo. Our data suggest that targeting the EGFR indirectly by inhibiting its cytoplasmic activators, the cytohesins, has the potential to improve the treatment of primarily EGFR-TKI resistant lung cancers.Anke BillAnton SchmitzKatharina KönigLukas C HeukampJeffrey S HannamMichael FamulokPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e41179 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anke Bill Anton Schmitz Katharina König Lukas C Heukamp Jeffrey S Hannam Michael Famulok Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.
description	Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib, have been proven to efficiently inhibit the proliferation of a subset of non small-cell lung cancers (NSCLC). Unfortunately, the majority of NSCLC expressing wild type EGFR is primarily resistant to EGFR-TKI treatment. Here, we show that the proliferation of the gefitinib-resistant NSCLC cell lines H460 and A549 is reduced by the small molecule SecinH3 which indirectly attenuates EGFR activation by inhibition of cytohesins, a class of recently discovered cytoplasmic EGFR activators. SecinH3 and gefitinib showed a synergistic antiproliferative effect, which correlated with a profound inhibition of Akt activation and survivin expression. Treating mice bearing H460 xenografts with SecinH3 showed the antiproliferative and pro-apoptotic effect of SecinH3 in vivo. Our data suggest that targeting the EGFR indirectly by inhibiting its cytoplasmic activators, the cytohesins, has the potential to improve the treatment of primarily EGFR-TKI resistant lung cancers.
format	article
author	Anke Bill Anton Schmitz Katharina König Lukas C Heukamp Jeffrey S Hannam Michael Famulok
author_facet	Anke Bill Anton Schmitz Katharina König Lukas C Heukamp Jeffrey S Hannam Michael Famulok
author_sort	Anke Bill
title	Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.
title_short	Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.
title_full	Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.
title_fullStr	Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.
title_full_unstemmed	Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.
title_sort	anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/abcd96ca8a6243b0bebc9a26e3465d5a
work_keys_str_mv	AT ankebill antiproliferativeeffectofcytohesininhibitioningefitinibresistantlungcancercells AT antonschmitz antiproliferativeeffectofcytohesininhibitioningefitinibresistantlungcancercells AT katharinakonig antiproliferativeeffectofcytohesininhibitioningefitinibresistantlungcancercells AT lukascheukamp antiproliferativeeffectofcytohesininhibitioningefitinibresistantlungcancercells AT jeffreyshannam antiproliferativeeffectofcytohesininhibitioningefitinibresistantlungcancercells AT michaelfamulok antiproliferativeeffectofcytohesininhibitioningefitinibresistantlungcancercells
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Anti-proliferative effect of cytohesin inhibition in gefitinib-resistant lung cancer cells.

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