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Sensitization of lung cancer cells by altered dimerization of HSP27

Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small m...

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Autores principales: Choi, Byeol, Choi, Seul-Ki, Park, You Na, Kwak, Soo-Yeon, Lee, Hwa Jeong, Kwon, Youngjoo, Na, Younghwa, Lee, Yun-Sil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739644/
https://www.ncbi.nlm.nih.gov/pubmed/29285257
http://dx.doi.org/10.18632/oncotarget.22192
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author Choi, Byeol
Choi, Seul-Ki
Park, You Na
Kwak, Soo-Yeon
Lee, Hwa Jeong
Kwon, Youngjoo
Na, Younghwa
Lee, Yun-Sil
author_facet Choi, Byeol
Choi, Seul-Ki
Park, You Na
Kwak, Soo-Yeon
Lee, Hwa Jeong
Kwon, Youngjoo
Na, Younghwa
Lee, Yun-Sil
author_sort Choi, Byeol
collection PubMed
description Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, small molecules with altered cross linking activity of HSP27, were identified to inhibit building a large oligomer led to sensitization in combination with radiation and chemotherapeutic drugs. In this study, a chromene compound, J2 that exhibited better cross-linking activity of HSP27 than xanthone compound, SW15 which was previously identified, was yielding sensitization to NSCLC cells with high expression of HSP27 when combined with HSP90 inhibitor and standard anticancer modalities such as taxol and cisplatin. In vivo xenograft system also showed sensitization activity of J2, as well as in vitro cell viability, cell death or apoptosis detection assay. For better druggability, several quinolone compounds, an (bio) isostere of chromone and one of well-known core in many marketed medicine, was designed and synthesized by replacement of oxygen with nitrogen in 4-pyron structure of J2. However, the cross linking activity of HSP27 disappeared by quinolone compounds and the sensitizing effects on the anticancer drugs disappeared as well, suggesting oxygene moiety of 4-pyron structure of J2 may be a pharmacophore for induction of cross linking of HSP27 and sensitization to cancer cells. In conclusion, combination of chemotherapy with small molecules that induces altered cross-linking of HSP27 may be a good strategy to overcome the resistance of anticancer drugs in HSP27-over-expressing cancer cells.
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spelling pubmed-57396442017-12-28 Sensitization of lung cancer cells by altered dimerization of HSP27 Choi, Byeol Choi, Seul-Ki Park, You Na Kwak, Soo-Yeon Lee, Hwa Jeong Kwon, Youngjoo Na, Younghwa Lee, Yun-Sil Oncotarget Research Paper Heat shock protein 27 (HSP27, HSPB1) induces resistance to anticancer drugs in various cancer types, including non-small cell lung cancer (NSCLC). Therefore, pharmacological inhibition of HSP27 in NSCLC may be a good strategy for anticancer therapy. Unlike other HSPs such as HSP90 and HSP70, small molecule approaches for neutralization of HSP27 are not well established because of the absence of an ATP binding domain. Previously, small molecules with altered cross linking activity of HSP27, were identified to inhibit building a large oligomer led to sensitization in combination with radiation and chemotherapeutic drugs. In this study, a chromene compound, J2 that exhibited better cross-linking activity of HSP27 than xanthone compound, SW15 which was previously identified, was yielding sensitization to NSCLC cells with high expression of HSP27 when combined with HSP90 inhibitor and standard anticancer modalities such as taxol and cisplatin. In vivo xenograft system also showed sensitization activity of J2, as well as in vitro cell viability, cell death or apoptosis detection assay. For better druggability, several quinolone compounds, an (bio) isostere of chromone and one of well-known core in many marketed medicine, was designed and synthesized by replacement of oxygen with nitrogen in 4-pyron structure of J2. However, the cross linking activity of HSP27 disappeared by quinolone compounds and the sensitizing effects on the anticancer drugs disappeared as well, suggesting oxygene moiety of 4-pyron structure of J2 may be a pharmacophore for induction of cross linking of HSP27 and sensitization to cancer cells. In conclusion, combination of chemotherapy with small molecules that induces altered cross-linking of HSP27 may be a good strategy to overcome the resistance of anticancer drugs in HSP27-over-expressing cancer cells. Impact Journals LLC 2017-10-31 /pmc/articles/PMC5739644/ /pubmed/29285257 http://dx.doi.org/10.18632/oncotarget.22192 Text en Copyright: © 2017 Choi 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
Choi, Byeol
Choi, Seul-Ki
Park, You Na
Kwak, Soo-Yeon
Lee, Hwa Jeong
Kwon, Youngjoo
Na, Younghwa
Lee, Yun-Sil
Sensitization of lung cancer cells by altered dimerization of HSP27
title Sensitization of lung cancer cells by altered dimerization of HSP27
title_full Sensitization of lung cancer cells by altered dimerization of HSP27
title_fullStr Sensitization of lung cancer cells by altered dimerization of HSP27
title_full_unstemmed Sensitization of lung cancer cells by altered dimerization of HSP27
title_short Sensitization of lung cancer cells by altered dimerization of HSP27
title_sort sensitization of lung cancer cells by altered dimerization of hsp27
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739644/
https://www.ncbi.nlm.nih.gov/pubmed/29285257
http://dx.doi.org/10.18632/oncotarget.22192
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