1. Combining disulfiram and poly(l-glutamic acid)-cisplatin conjugates for combating cisplatin resistance.
- Author
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Song W, Tang Z, Shen N, Yu H, Jia Y, Zhang D, Jiang J, He C, Tian H, and Chen X
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Apoptosis, Cell Line, Tumor, Cell Survival, Cisplatin chemistry, Cisplatin therapeutic use, Disulfiram chemistry, Disulfiram therapeutic use, Female, Glutathione metabolism, Heterografts, Humans, Mice, Inbred BALB C, Mice, Nude, Nanoparticles chemistry, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, bcl-2-Associated X Protein metabolism, NF-kappaB-Inducing Kinase, Antineoplastic Agents pharmacology, Cisplatin pharmacology, Disulfiram pharmacology, Drug Resistance, Neoplasm drug effects, Polyglutamic Acid chemistry
- Abstract
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., (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Published
- 2016
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