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Synergism between thioredoxin reductase inhibitor ethaselen and sodium selenite in inhibiting proliferation and inducing death of human non-small cell lung cancer cells
New effective treatment for human non-small cell lung cancer (NSCLC) is needed. The thioredoxin (Trx) system composes of thioredoxin reductase (TrxR), Trx and NADPH. In this study, we combined an organic selenium compound--TrxR inhibitor ethaselen (BBSKE) with low dosage sodium selenite to inhibit p...
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| Published in: | Chemico-biological interactions 2017-09, Vol.275, p.74-85 |
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| creator | Zheng, Xiaoqing Xu, Wei Sun, Ruoxuan Yin, Hanwei Dong, Chaoran Zeng, Huihui |
| description | New effective treatment for human non-small cell lung cancer (NSCLC) is needed. The thioredoxin (Trx) system composes of thioredoxin reductase (TrxR), Trx and NADPH. In this study, we combined an organic selenium compound--TrxR inhibitor ethaselen (BBSKE) with low dosage sodium selenite to inhibit proliferation and induce death of NSCLC cells, and identified underlying mechanisms. Synergistic anti-proliferation effect of BBSKE and selenite was found in human NSCLC cell lines, A549, NCI-H1299 and NCI-1266. A significant increase of apoptosis, necrosis and autophagy were observed in the group of BBSKE plus selenite in A549 cells. The autophagy induced by BBSKE and selenite inhibited apoptosis and necrosis. In addition, BBSKE plus selenite induced G2/M arrest, which was verified by the alteration of gene and protein expression of cell cycle regulatory complexes. The intracellular enzyme activity of TrxR was remarkably decreased by cotreatment of BBSKE and selenite. Besides, the mRNA and protein level of TrxR1 and Trx1 were significantly inhibited by cotreatment of BBSKE and selenite. HEK 293 cells overexpressing TrxR1 were more sensitive to BBSKE plus selenite. The nuclear translocation of Trx1 and Ref-1, as well as expression of Ref-1 and AP-1 were inhibited by combination treatment. In short, BBSKE synergizes selenite in inhibiting proliferation and inducing death of NSCLC cells; BBSKE combined with selenite may be a treatment strategy for NSCLC.
•BBSKE and selenite synergistically inhibited proliferation in three NSCLC cell lines.•BBSKE plus selenite induced apoptosis, necrosis and autophagy in A549 cells.•G2/M arrest was observed after BBSKE and selenite treatment.•TrxR activity, TrxR1 and Trx1 expression were remarkably attenuated.•Ref-1, AP-1 expression, and nuclear translocation of Trx and Ref-1 were inhibited. |
| doi_str_mv | 10.1016/j.cbi.2017.07.020 |
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•BBSKE and selenite synergistically inhibited proliferation in three NSCLC cell lines.•BBSKE plus selenite induced apoptosis, necrosis and autophagy in A549 cells.•G2/M arrest was observed after BBSKE and selenite treatment.•TrxR activity, TrxR1 and Trx1 expression were remarkably attenuated.•Ref-1, AP-1 expression, and nuclear translocation of Trx and Ref-1 were inhibited.</description><identifier>ISSN: 0009-2797</identifier><identifier>EISSN: 1872-7786</identifier><identifier>DOI: 10.1016/j.cbi.2017.07.020</identifier><identifier>PMID: 28757135</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>A549 Cells ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Autophagy ; Autophagy - drug effects ; Bridged Bicyclo Compounds, Heterocyclic - chemistry ; Bridged Bicyclo Compounds, Heterocyclic - pharmacology ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell Cycle Checkpoints - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Drug Synergism ; HEK293 Cells ; Humans ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Microtubule-Associated Proteins - metabolism ; Necrosis ; Organoselenium Compounds - chemistry ; Organoselenium Compounds - pharmacology ; Ref-1/AP-1 pathway ; RNA-Binding Proteins - metabolism ; Sodium selenite ; Sodium Selenite - chemistry ; Sodium Selenite - pharmacology ; Thioredoxin reductase (TrxR) ; Thioredoxin-Disulfide Reductase - antagonists & inhibitors ; Thioredoxin-Disulfide Reductase - metabolism ; Thioredoxins - genetics ; Thioredoxins - metabolism ; Transcription Factor AP-1 - genetics ; Transcription Factor AP-1 - metabolism</subject><ispartof>Chemico-biological interactions, 2017-09, Vol.275, p.74-85</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-fca7ebf4161451a4faaa6e24b9d44901470ef969a6747613f7a2ca67946df2233</citedby><cites>FETCH-LOGICAL-c353t-fca7ebf4161451a4faaa6e24b9d44901470ef969a6747613f7a2ca67946df2233</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28757135$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zheng, Xiaoqing</creatorcontrib><creatorcontrib>Xu, Wei</creatorcontrib><creatorcontrib>Sun, Ruoxuan</creatorcontrib><creatorcontrib>Yin, Hanwei</creatorcontrib><creatorcontrib>Dong, Chaoran</creatorcontrib><creatorcontrib>Zeng, Huihui</creatorcontrib><title>Synergism between thioredoxin reductase inhibitor ethaselen and sodium selenite in inhibiting proliferation and inducing death of human non-small cell lung cancer cells</title><title>Chemico-biological interactions</title><addtitle>Chem Biol Interact</addtitle><description>New effective treatment for human non-small cell lung cancer (NSCLC) is needed. The thioredoxin (Trx) system composes of thioredoxin reductase (TrxR), Trx and NADPH. In this study, we combined an organic selenium compound--TrxR inhibitor ethaselen (BBSKE) with low dosage sodium selenite to inhibit proliferation and induce death of NSCLC cells, and identified underlying mechanisms. Synergistic anti-proliferation effect of BBSKE and selenite was found in human NSCLC cell lines, A549, NCI-H1299 and NCI-1266. A significant increase of apoptosis, necrosis and autophagy were observed in the group of BBSKE plus selenite in A549 cells. The autophagy induced by BBSKE and selenite inhibited apoptosis and necrosis. In addition, BBSKE plus selenite induced G2/M arrest, which was verified by the alteration of gene and protein expression of cell cycle regulatory complexes. The intracellular enzyme activity of TrxR was remarkably decreased by cotreatment of BBSKE and selenite. Besides, the mRNA and protein level of TrxR1 and Trx1 were significantly inhibited by cotreatment of BBSKE and selenite. HEK 293 cells overexpressing TrxR1 were more sensitive to BBSKE plus selenite. The nuclear translocation of Trx1 and Ref-1, as well as expression of Ref-1 and AP-1 were inhibited by combination treatment. In short, BBSKE synergizes selenite in inhibiting proliferation and inducing death of NSCLC cells; BBSKE combined with selenite may be a treatment strategy for NSCLC.
•BBSKE and selenite synergistically inhibited proliferation in three NSCLC cell lines.•BBSKE plus selenite induced apoptosis, necrosis and autophagy in A549 cells.•G2/M arrest was observed after BBSKE and selenite treatment.•TrxR activity, TrxR1 and Trx1 expression were remarkably attenuated.•Ref-1, AP-1 expression, and nuclear translocation of Trx and Ref-1 were inhibited.</description><subject>A549 Cells</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - chemistry</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Drug Synergism</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Microtubule-Associated Proteins - metabolism</subject><subject>Necrosis</subject><subject>Organoselenium Compounds - chemistry</subject><subject>Organoselenium Compounds - pharmacology</subject><subject>Ref-1/AP-1 pathway</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Sodium selenite</subject><subject>Sodium Selenite - chemistry</subject><subject>Sodium Selenite - pharmacology</subject><subject>Thioredoxin reductase (TrxR)</subject><subject>Thioredoxin-Disulfide Reductase - antagonists & inhibitors</subject><subject>Thioredoxin-Disulfide Reductase - metabolism</subject><subject>Thioredoxins - genetics</subject><subject>Thioredoxins - metabolism</subject><subject>Transcription Factor AP-1 - genetics</subject><subject>Transcription Factor AP-1 - metabolism</subject><issn>0009-2797</issn><issn>1872-7786</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNp9kc9u1DAQxi0EotvCA3BBPnLJYjteOxEnVPFPqsQBOFuOM25mldjFdqB9Ix4Tp9tyRBp5NOPffBr7I-QVZ3vOuHp73LsB94JxvWc1BHtCdrzTotG6U0_JjjHWN0L3-oyc53ysJROSPSdnotMHzdvDjvz5dhcgXWNe6ADlN0CgZcKYYIy3GGjNqys2A8Uw4YAlJgplqo25kjaMNMcR14XeN7Bs3COK4ZrepDijh2QLxhOPoSpuVyPYMtHo6bQuNtAQQ5MXO8_UQT3mtSLOBgfpvpFfkGfezhlePuQL8uPjh--Xn5urr5--XL6_alx7aEvjndUweMkVlwdupbfWKhBy6Ecpe8alZuB71VulpVa89doKV4teqtEL0bYX5M1Jt67-c4VczIJ528AGiGs2vBey65VgXUX5CXUp5pzAm5uEi013hjOzGWSOphpkNoMMqyFYnXn9IL8OC4z_Jh4dqcC7EwD1kb8QkskOof7DiAlcMWPE_8j_BVxfpSg</recordid><startdate>20170925</startdate><enddate>20170925</enddate><creator>Zheng, Xiaoqing</creator><creator>Xu, Wei</creator><creator>Sun, Ruoxuan</creator><creator>Yin, Hanwei</creator><creator>Dong, Chaoran</creator><creator>Zeng, Huihui</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20170925</creationdate><title>Synergism between thioredoxin reductase inhibitor ethaselen and sodium selenite in inhibiting proliferation and inducing death of human non-small cell lung cancer cells</title><author>Zheng, Xiaoqing ; Xu, Wei ; Sun, Ruoxuan ; Yin, Hanwei ; Dong, Chaoran ; Zeng, Huihui</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-fca7ebf4161451a4faaa6e24b9d44901470ef969a6747613f7a2ca67946df2233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>A549 Cells</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Autophagy</topic><topic>Autophagy - drug effects</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - chemistry</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Cell Cycle Checkpoints - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Drug Synergism</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Microtubule-Associated Proteins - metabolism</topic><topic>Necrosis</topic><topic>Organoselenium Compounds - chemistry</topic><topic>Organoselenium Compounds - pharmacology</topic><topic>Ref-1/AP-1 pathway</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Sodium selenite</topic><topic>Sodium Selenite - chemistry</topic><topic>Sodium Selenite - pharmacology</topic><topic>Thioredoxin reductase (TrxR)</topic><topic>Thioredoxin-Disulfide Reductase - antagonists & inhibitors</topic><topic>Thioredoxin-Disulfide Reductase - metabolism</topic><topic>Thioredoxins - genetics</topic><topic>Thioredoxins - metabolism</topic><topic>Transcription Factor AP-1 - genetics</topic><topic>Transcription Factor AP-1 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zheng, Xiaoqing</creatorcontrib><creatorcontrib>Xu, Wei</creatorcontrib><creatorcontrib>Sun, Ruoxuan</creatorcontrib><creatorcontrib>Yin, Hanwei</creatorcontrib><creatorcontrib>Dong, Chaoran</creatorcontrib><creatorcontrib>Zeng, Huihui</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Chemico-biological interactions</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zheng, Xiaoqing</au><au>Xu, Wei</au><au>Sun, Ruoxuan</au><au>Yin, Hanwei</au><au>Dong, Chaoran</au><au>Zeng, Huihui</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synergism between thioredoxin reductase inhibitor ethaselen and sodium selenite in inhibiting proliferation and inducing death of human non-small cell lung cancer cells</atitle><jtitle>Chemico-biological interactions</jtitle><addtitle>Chem Biol Interact</addtitle><date>2017-09-25</date><risdate>2017</risdate><volume>275</volume><spage>74</spage><epage>85</epage><pages>74-85</pages><issn>0009-2797</issn><eissn>1872-7786</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>New effective treatment for human non-small cell lung cancer (NSCLC) is needed. The thioredoxin (Trx) system composes of thioredoxin reductase (TrxR), Trx and NADPH. In this study, we combined an organic selenium compound--TrxR inhibitor ethaselen (BBSKE) with low dosage sodium selenite to inhibit proliferation and induce death of NSCLC cells, and identified underlying mechanisms. Synergistic anti-proliferation effect of BBSKE and selenite was found in human NSCLC cell lines, A549, NCI-H1299 and NCI-1266. A significant increase of apoptosis, necrosis and autophagy were observed in the group of BBSKE plus selenite in A549 cells. The autophagy induced by BBSKE and selenite inhibited apoptosis and necrosis. In addition, BBSKE plus selenite induced G2/M arrest, which was verified by the alteration of gene and protein expression of cell cycle regulatory complexes. The intracellular enzyme activity of TrxR was remarkably decreased by cotreatment of BBSKE and selenite. Besides, the mRNA and protein level of TrxR1 and Trx1 were significantly inhibited by cotreatment of BBSKE and selenite. HEK 293 cells overexpressing TrxR1 were more sensitive to BBSKE plus selenite. The nuclear translocation of Trx1 and Ref-1, as well as expression of Ref-1 and AP-1 were inhibited by combination treatment. In short, BBSKE synergizes selenite in inhibiting proliferation and inducing death of NSCLC cells; BBSKE combined with selenite may be a treatment strategy for NSCLC.
•BBSKE and selenite synergistically inhibited proliferation in three NSCLC cell lines.•BBSKE plus selenite induced apoptosis, necrosis and autophagy in A549 cells.•G2/M arrest was observed after BBSKE and selenite treatment.•TrxR activity, TrxR1 and Trx1 expression were remarkably attenuated.•Ref-1, AP-1 expression, and nuclear translocation of Trx and Ref-1 were inhibited.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>28757135</pmid><doi>10.1016/j.cbi.2017.07.020</doi><tpages>12</tpages></addata></record> |
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| subjects | A549 Cells Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Autophagy Autophagy - drug effects Bridged Bicyclo Compounds, Heterocyclic - chemistry Bridged Bicyclo Compounds, Heterocyclic - pharmacology Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Cycle Checkpoints - drug effects Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Drug Synergism HEK293 Cells Humans Lung Neoplasms - metabolism Lung Neoplasms - pathology Microtubule-Associated Proteins - metabolism Necrosis Organoselenium Compounds - chemistry Organoselenium Compounds - pharmacology Ref-1/AP-1 pathway RNA-Binding Proteins - metabolism Sodium selenite Sodium Selenite - chemistry Sodium Selenite - pharmacology Thioredoxin reductase (TrxR) Thioredoxin-Disulfide Reductase - antagonists & inhibitors Thioredoxin-Disulfide Reductase - metabolism Thioredoxins - genetics Thioredoxins - metabolism Transcription Factor AP-1 - genetics Transcription Factor AP-1 - metabolism |
| title | Synergism between thioredoxin reductase inhibitor ethaselen and sodium selenite in inhibiting proliferation and inducing death of human non-small cell lung cancer cells |
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