Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts.
BACKGROUND: Chromosome Region Maintenance 1 (CRM1) is a nuclear exporter and its inhibitor has anti-tumor activity in various cancers. This study assessed the therapeutic efficiency of the novel CRM1 inhibitor KPT-185 on non-small cell lung cancer (NSCLC). METHODS: NSCLC cell lines were treated with...
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doaj-82f15ac59f4347dc9c6161a96dd6cb5d2020-11-24T21:50:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0193e8984810.1371/journal.pone.0089848Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts.Shuai WangXiaohong HanJianfei WangJiarui YaoYuankai ShiBACKGROUND: Chromosome Region Maintenance 1 (CRM1) is a nuclear exporter and its inhibitor has anti-tumor activity in various cancers. This study assessed the therapeutic efficiency of the novel CRM1 inhibitor KPT-185 on non-small cell lung cancer (NSCLC). METHODS: NSCLC cell lines were treated with KPT-185 to assess changes in cell viability, cell cycle, apoptosis, and protein expression. NOD-SCID mice carrying NSCLC cell xenografts were orally treated with KPT-276, a clinical analog of KPT-185, to examine the efficacy and side effects of KPT-276 in vivo. RESULTS: KPT-185 significantly reduced the viability of six NSCLC cell lines in a time- and dose-dependent manner, including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant H1975 and H1650GR cell lines. In addition, KPT-185 induced these NSCLC cells to arrest at G1 phase of the cell cycle and caused apoptosis in a dose-dependent manner. KPT-185 treatment also reduced CRM1 protein levels in six NSCLC cell lines, and the reduction could be completely abolished by the proteasome inhibitor bortezomib. KPT-185 activated caspase 3, 8, and 9, but inhibited survivin expression in NSCLC cells. In a mouse H1975 cell xenograft model, tumor growth was significantly inhibited by oral KPT-276 administration, and there was no significant mouse body weight loss or other side effects. CONCLUSIONS: The current study demonstrated the anti-tumor effects of KPT-185 in NSCLC cells, including EGFR-TKI-resistant NSCLC cell lines. Further studies will assess anti-tumor activity of KPT-185 in a clinical trial for NSCLC patients.http://europepmc.org/articles/PMC3942386?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shuai Wang Xiaohong Han Jianfei Wang Jiarui Yao Yuankai Shi |
spellingShingle |
Shuai Wang Xiaohong Han Jianfei Wang Jiarui Yao Yuankai Shi Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. PLoS ONE |
author_facet |
Shuai Wang Xiaohong Han Jianfei Wang Jiarui Yao Yuankai Shi |
author_sort |
Shuai Wang |
title |
Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. |
title_short |
Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. |
title_full |
Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. |
title_fullStr |
Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. |
title_full_unstemmed |
Antitumor effects of a novel chromosome region maintenance 1 (CRM1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. |
title_sort |
antitumor effects of a novel chromosome region maintenance 1 (crm1) inhibitor on non-small cell lung cancer cells in vitro and in mouse tumor xenografts. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
BACKGROUND: Chromosome Region Maintenance 1 (CRM1) is a nuclear exporter and its inhibitor has anti-tumor activity in various cancers. This study assessed the therapeutic efficiency of the novel CRM1 inhibitor KPT-185 on non-small cell lung cancer (NSCLC). METHODS: NSCLC cell lines were treated with KPT-185 to assess changes in cell viability, cell cycle, apoptosis, and protein expression. NOD-SCID mice carrying NSCLC cell xenografts were orally treated with KPT-276, a clinical analog of KPT-185, to examine the efficacy and side effects of KPT-276 in vivo. RESULTS: KPT-185 significantly reduced the viability of six NSCLC cell lines in a time- and dose-dependent manner, including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant H1975 and H1650GR cell lines. In addition, KPT-185 induced these NSCLC cells to arrest at G1 phase of the cell cycle and caused apoptosis in a dose-dependent manner. KPT-185 treatment also reduced CRM1 protein levels in six NSCLC cell lines, and the reduction could be completely abolished by the proteasome inhibitor bortezomib. KPT-185 activated caspase 3, 8, and 9, but inhibited survivin expression in NSCLC cells. In a mouse H1975 cell xenograft model, tumor growth was significantly inhibited by oral KPT-276 administration, and there was no significant mouse body weight loss or other side effects. CONCLUSIONS: The current study demonstrated the anti-tumor effects of KPT-185 in NSCLC cells, including EGFR-TKI-resistant NSCLC cell lines. Further studies will assess anti-tumor activity of KPT-185 in a clinical trial for NSCLC patients. |
url |
http://europepmc.org/articles/PMC3942386?pdf=render |
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