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Polyester-Based Dendrimer Nanoparticles Combined with Etoposide Have an Improved Cytotoxic and Pro-Oxidant Effect on Human Neuroblastoma Cells.

ABSTRACT: Etoposide (ETO) is a cytotoxic drug that exerts its effect by increasing reactive oxygen species (ROS) production. Although ETO is widely used, fast metabolism, poor solubility, systemic toxicity, and multi-drug resistance induction all limit its administration dosage and its therapeutic efficiency. In order to address these issues, a biodegradable dendrimer was prepared for entrapping and protecting ETO and for enhancing its solubility and effectiveness. The achieved dendrimer complex with ETO (CPX 5) showed the typical properties of a well-functioning delivery system, i.e., nanospherical morphology (70 nm), optimal Z-potential (-45 mV), good drug loading (37%), very satisfying entrapment efficiency (53%), and a remarkably improved solubility in biocompatible solvents. In regards to its cytotoxic activity, CPX 5 was tested on neuroblastoma (NB) cells with very promising results. In fact, the dendrimer scaffold and ETO are able to exert per se a cytotoxic and pro-oxidant activity on human NB cells. When CPX 5 is combined with ETO, it shows a synergistic action, slowly releasing the drug over time and significantly improving and protracting bioactivity. On the basis of these findings, the prepared ETO reservoir represents a novel biodegradable and promising device for the delivery of ETO into NB cells.

SUBMITTER: Alfei S

PROVIDER: S-EPMC7022520 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Polyester-Based Dendrimer Nanoparticles Combined with Etoposide Have an Improved Cytotoxic and Pro-Oxidant Effect on Human Neuroblastoma Cells.

Alfei Silvana S Marengo Barbara B Domenicotti Cinzia C

Antioxidants (Basel, Switzerland) 20200106 1

Etoposide (ETO) is a cytotoxic drug that exerts its effect by increasing reactive oxygen species (ROS) production. Although ETO is widely used, fast metabolism, poor solubility, systemic toxicity, and multi-drug resistance induction all limit its administration dosage and its therapeutic efficiency. In order to address these issues, a biodegradable dendrimer was prepared for entrapping and protecting ETO and for enhancing its solubility and effectiveness. The achieved dendrimer complex with ETO ...[more]

PMID: 31935872

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Project description:High-risk neuroblastoma remains a therapeutic challenge with a long-term survival rate of less than 40%. Therefore, new agents are urgently needed to overcome chemotherapy resistance so as to improve the treatment outcome of this deadly disease. Histone deacetylase (HDAC) inhibitors (HDACIs) represent a novel class of anticancer drugs. Recent studies demonstrated that HDACIs can down-regulate the CHK1 pathway by which cancer cells can develop resistance to conventional chemotherapy drugs. This prompted our hypothesis that combining HDACIs with DNA damaging chemotherapeutic drugs for treating neuroblastoma would result in enhanced anti-tumor activities of these drugs. Treatment of high-risk neuroblastoma cell lines with a novel pan-HDACI, panobinostat (LBH589), resulted in dose-dependent growth arrest and apoptosis in 4 high-risk neuroblastoma cell lines. Further, the combination of panobinostat with cisplatin, doxorubicin, or etoposide resulted in highly synergistic antitumor interactions in the high-risk neuroblastoma cell lines, independent of the sequence of drug administration. This was accompanied by cooperative induction of apoptosis. Furthermore, panobinostat treatment resulted in substantial down-regulation of CHK1 and its downstream pathway and abrogation of the G2 cell cycle checkpoint. Synergistic antitumor interactions were also observed when the DNA damaging agents were combined with a CHK1-specific inhibitor, LY2603618. Contrary to panobinostat treatment, LY2603618 treatments neither resulted in abrogation of the G2 cell cycle checkpoint nor enhanced cisplatin, doxorubicin, or etoposide-induced apoptosis in the high-risk neuroblastoma cells. Surprisingly, LY2603618 treatments caused substantial down-regulation of total CDK1. Despite this discrepancy between panobinostat and LY2603618, our results indicate that suppression of the CHK1 pathway by panobinostat is at least partially responsible for the synergistic antitumor interactions between panobinostat and the DNA damaging agents in high-risk neuroblastoma cells. The results of this study provide a rationale for clinical evaluation of the combination of panobinostat and cisplatin, doxorubicin, or etoposide for treating children with high-risk neuroblastoma.

Dataset Information

Polyester-Based Dendrimer Nanoparticles Combined with Etoposide Have an Improved Cytotoxic and Pro-Oxidant Effect on Human Neuroblastoma Cells.

Publications

Polyester-Based Dendrimer Nanoparticles Combined with Etoposide Have an Improved Cytotoxic and Pro-Oxidant Effect on Human Neuroblastoma Cells.

Similar Datasets

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