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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
Main Authors: Song, Wantong, Tang, Zhaohui, Shen, Na, Yu, Haiyang, Jia, Yanjie, Zhang, Dawei, Jiang, Jian, He, Chaoliang, Tian, Huayu, Chen, Xuesi
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cited_by cdi_FETCH-LOGICAL-c468t-878451efcc756b305782fb93b0eae79ff30bd21e28bd66d9661c956022569f603
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container_title Journal of controlled release
container_volume 231
creator Song, Wantong
Tang, Zhaohui
Shen, Na
Yu, Haiyang
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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. [Display omitted]
doi_str_mv 10.1016/j.jconrel.2016.02.039
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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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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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