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Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance
A poly(l-glutamic acid) graft polyethylene glycol-cisplatin complex (PGA-CisPt) performs well in reducing the toxicity of free cisplatin and greatly enhances the accumulation and retention of cisplatin in solid tumors. However, there is a lack of effective treatment options for cisplatin-resistant t...
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Published in: | Journal of controlled release 2016-06, Vol.231, p.94-102 |
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creator | Song, Wantong Tang, Zhaohui Shen, Na Yu, Haiyang Jia, Yanjie Zhang, Dawei Jiang, Jian He, Chaoliang Tian, Huayu Chen, Xuesi |
description | A poly(l-glutamic acid) graft polyethylene glycol-cisplatin complex (PGA-CisPt) performs well in reducing the toxicity of free cisplatin and greatly enhances the accumulation and retention of cisplatin in solid tumors. However, there is a lack of effective treatment options for cisplatin-resistant tumors. A major reason for this is the dense PEG shell, which ensures that the PGA-CisPt maintains a long retention time in the blood that may result in it bypassing the tumor cells or failing to be endocytosed within the tumor microenvironment. Consequently, the cisplatin from PGA-CisPt is released to the extracellular space in the presence of cisplatin-resistant tumor cells and the resistant problem to free cisplatin still valid. Therefore, we devised a strategy to combat the resistance of cisplatin in the tumor microenvironment using nanoparticles-loaded disulfiram (NPs-DSF) as a modulator. In vitro, cisplatin, in combination with DSF, had a synergistic effect and decreased cell survival rate of cisplatin-resistant A549DDP cells. This effect was also observed when combining PGA-CisPt with NPs-DSF. Similarly, in Balb/C nude mice with A549DDP xenografts, NPs-DSF improved PGA-CisPt effectiveness in inhibiting tumor growth while maintaining low toxicity. Our data demonstrate that DSF reduces intracellular glutathione (GSH) levels, inhibits NFκB activity, and modulates the expression of apoptosis-related proteins Bcl-2 and Bax, thereby improves the effectiveness of cisplatin in resistant cell lines. Here, we provide a promising method for overcoming cisplatin resistance in tumors, while maintaining the in vivo benefits of the PGA-CisPt complex.
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doi_str_mv | 10.1016/j.jconrel.2016.02.039 |
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[Display omitted]</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2016.02.039</identifier><identifier>PMID: 26928530</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Apoptosis ; bcl-2-Associated X Protein - metabolism ; Cell Line, Tumor ; Cell Survival ; Cisplatin ; Cisplatin - chemistry ; Cisplatin - pharmacology ; Cisplatin - therapeutic use ; Combination ; Disulfiram ; Disulfiram - chemistry ; Disulfiram - pharmacology ; Disulfiram - therapeutic use ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Female ; Glutathione - metabolism ; Heterografts ; Humans ; Mice, Inbred BALB C ; Mice, Nude ; Nanoparticles ; Nanoparticles - chemistry ; NF-kappaB-Inducing Kinase ; Polyglutamic Acid - chemistry ; Protein Serine-Threonine Kinases - metabolism ; Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><ispartof>Journal of controlled release, 2016-06, Vol.231, p.94-102</ispartof><rights>2016 Elsevier B.V.</rights><rights>Copyright © 2016 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c468t-878451efcc756b305782fb93b0eae79ff30bd21e28bd66d9661c956022569f603</citedby><cites>FETCH-LOGICAL-c468t-878451efcc756b305782fb93b0eae79ff30bd21e28bd66d9661c956022569f603</cites><orcidid>0000-0003-3542-9256</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26928530$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Wantong</creatorcontrib><creatorcontrib>Tang, Zhaohui</creatorcontrib><creatorcontrib>Shen, Na</creatorcontrib><creatorcontrib>Yu, Haiyang</creatorcontrib><creatorcontrib>Jia, Yanjie</creatorcontrib><creatorcontrib>Zhang, Dawei</creatorcontrib><creatorcontrib>Jiang, Jian</creatorcontrib><creatorcontrib>He, Chaoliang</creatorcontrib><creatorcontrib>Tian, Huayu</creatorcontrib><creatorcontrib>Chen, Xuesi</creatorcontrib><title>Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>A poly(l-glutamic acid) graft polyethylene glycol-cisplatin complex (PGA-CisPt) performs well in reducing the toxicity of free cisplatin and greatly enhances the accumulation and retention of cisplatin in solid tumors. However, there is a lack of effective treatment options for cisplatin-resistant tumors. A major reason for this is the dense PEG shell, which ensures that the PGA-CisPt maintains a long retention time in the blood that may result in it bypassing the tumor cells or failing to be endocytosed within the tumor microenvironment. Consequently, the cisplatin from PGA-CisPt is released to the extracellular space in the presence of cisplatin-resistant tumor cells and the resistant problem to free cisplatin still valid. Therefore, we devised a strategy to combat the resistance of cisplatin in the tumor microenvironment using nanoparticles-loaded disulfiram (NPs-DSF) as a modulator. In vitro, cisplatin, in combination with DSF, had a synergistic effect and decreased cell survival rate of cisplatin-resistant A549DDP cells. This effect was also observed when combining PGA-CisPt with NPs-DSF. Similarly, in Balb/C nude mice with A549DDP xenografts, NPs-DSF improved PGA-CisPt effectiveness in inhibiting tumor growth while maintaining low toxicity. Our data demonstrate that DSF reduces intracellular glutathione (GSH) levels, inhibits NFκB activity, and modulates the expression of apoptosis-related proteins Bcl-2 and Bax, thereby improves the effectiveness of cisplatin in resistant cell lines. Here, we provide a promising method for overcoming cisplatin resistance in tumors, while maintaining the in vivo benefits of the PGA-CisPt complex.
[Display omitted]</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival</subject><subject>Cisplatin</subject><subject>Cisplatin - chemistry</subject><subject>Cisplatin - pharmacology</subject><subject>Cisplatin - therapeutic use</subject><subject>Combination</subject><subject>Disulfiram</subject><subject>Disulfiram - chemistry</subject><subject>Disulfiram - pharmacology</subject><subject>Disulfiram - therapeutic use</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Female</subject><subject>Glutathione - metabolism</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Nanoparticles</subject><subject>Nanoparticles - chemistry</subject><subject>NF-kappaB-Inducing Kinase</subject><subject>Polyglutamic Acid - chemistry</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNqFkE1r3DAQhkVoyG62_QktPiYHO_pYydKplCVpCgu9JGchS6NFRra3kl3Iv4-W3bbHnsRonpmXeRD6THBDMBEPfdPbaUwQG1rKBtMGM3WF1kS2rN4qxT-gdWnImgmuVug25x5jzNm2vUErKhSVnOE18rtp6MIYxkPlQl6iD8kMlRlddZzi212sD3GZzRBsZWxw97UN-RjNHMaqpPfLwcyQKz-lUg7d6f9Q_UMS5JBnM1r4iK69iRk-Xd4Nen16fNk91_uf33_svu1ruxVyrmUrt5yAt7blomOYt5L6TrEOg4FWec9w5ygBKjsnhFNCEKu4wJRyobzAbIPuznuPafq1QJ71ELKFGM0I05I1kVi2VFFGCsrPqE1Tzgm8PqYwmPSmCdYnxbrXF8X6pFhjqoviMvflErF0A7i_U3-cFuDrGYBy6O8ASWcboEhwIYGdtZvCfyLeAdW8kRM</recordid><startdate>20160610</startdate><enddate>20160610</enddate><creator>Song, Wantong</creator><creator>Tang, Zhaohui</creator><creator>Shen, Na</creator><creator>Yu, Haiyang</creator><creator>Jia, Yanjie</creator><creator>Zhang, Dawei</creator><creator>Jiang, Jian</creator><creator>He, Chaoliang</creator><creator>Tian, Huayu</creator><creator>Chen, Xuesi</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><orcidid>https://orcid.org/0000-0003-3542-9256</orcidid></search><sort><creationdate>20160610</creationdate><title>Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance</title><author>Song, Wantong ; 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However, there is a lack of effective treatment options for cisplatin-resistant tumors. A major reason for this is the dense PEG shell, which ensures that the PGA-CisPt maintains a long retention time in the blood that may result in it bypassing the tumor cells or failing to be endocytosed within the tumor microenvironment. Consequently, the cisplatin from PGA-CisPt is released to the extracellular space in the presence of cisplatin-resistant tumor cells and the resistant problem to free cisplatin still valid. Therefore, we devised a strategy to combat the resistance of cisplatin in the tumor microenvironment using nanoparticles-loaded disulfiram (NPs-DSF) as a modulator. In vitro, cisplatin, in combination with DSF, had a synergistic effect and decreased cell survival rate of cisplatin-resistant A549DDP cells. This effect was also observed when combining PGA-CisPt with NPs-DSF. Similarly, in Balb/C nude mice with A549DDP xenografts, NPs-DSF improved PGA-CisPt effectiveness in inhibiting tumor growth while maintaining low toxicity. Our data demonstrate that DSF reduces intracellular glutathione (GSH) levels, inhibits NFκB activity, and modulates the expression of apoptosis-related proteins Bcl-2 and Bax, thereby improves the effectiveness of cisplatin in resistant cell lines. Here, we provide a promising method for overcoming cisplatin resistance in tumors, while maintaining the in vivo benefits of the PGA-CisPt complex.
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subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis bcl-2-Associated X Protein - metabolism Cell Line, Tumor Cell Survival Cisplatin Cisplatin - chemistry Cisplatin - pharmacology Cisplatin - therapeutic use Combination Disulfiram Disulfiram - chemistry Disulfiram - pharmacology Disulfiram - therapeutic use Drug resistance Drug Resistance, Neoplasm - drug effects Female Glutathione - metabolism Heterografts Humans Mice, Inbred BALB C Mice, Nude Nanoparticles Nanoparticles - chemistry NF-kappaB-Inducing Kinase Polyglutamic Acid - chemistry Protein Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins c-bcl-2 - metabolism |
title | Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance |
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