Ellipticine-loaded apoferritin nanocarrier retains DNA adduct-based cytochrome P450-facilitated toxicity in neuroblastoma cells
Language English Country Ireland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
101126/Z/13/Z
Wellcome Trust - United Kingdom
101126/Z/13/Z
Wellcome Trust - United Kingdom
PubMed
30914192
DOI
10.1016/j.tox.2019.03.009
PII: S0300-483X(18)30661-9
Knihovny.cz E-resources
- Keywords
- Apoferritin nanoparticles, Cytochrome P450-mediated metabolism, Cytotoxicity, DNA adducts, Ellipticine, Neuroblastoma,
- MeSH
- DNA Adducts genetics metabolism MeSH
- Apoferritins chemistry pharmacology MeSH
- Cytochrome P-450 CYP3A metabolism MeSH
- Ellipticines chemistry pharmacology MeSH
- Phosphorylation MeSH
- Histones metabolism MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Nanoparticles * MeSH
- Neuroblastoma drug therapy enzymology genetics pathology MeSH
- Drug Carriers * MeSH
- Drug Compounding MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Drug Liberation MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- Apoferritins MeSH
- CYP3A4 protein, human MeSH Browser
- Cytochrome P-450 CYP3A MeSH
- Ellipticines MeSH
- ellipticine MeSH Browser
- H2AX protein, human MeSH Browser
- Histones MeSH
- Drug Carriers * MeSH
- Antineoplastic Agents MeSH
Although ellipticine (Elli) is an efficient anticancer agent, it exerts several adverse effects. One approach to decrease the adverse effects of drugs is their encapsulation inside a suitable nanocarrier, allowing targeted delivery to tumour tissue whereas avoiding healthy cells. We constructed a nanocarrier from apoferritin (Apo) bearing ellipticine, ApoElli, and subsequently characterized. The nanocarrier exhibits a narrow size distribution suggesting its suitability for entrapping the hydrophobic ellipticine molecule. Ellipticine was released from ApoElli into the water environment under pH 6.5, but only less than 20% was released at pH 7.4. The interaction of ApoElli with microsomal membrane particles containing cytochrome P450 (CYP) biotransformation enzymes accelerated the release of ellipticine from this nanocarrier making it possible to be transferred into this membrane system even at pH 7.4 and facilitating CYP-mediated metabolism. Reactive metabolites were formed not only from free ellipticine, but also from ApoElli, and both generated covalent DNA adducts. ApoElli was toxic in UKF-NB-4 neuroblastoma cells, but showed significantly lower cytotoxicity in non-malignant fibroblast HDFn cells. Ellipticine either free or released from ApoElli was concentrated in the nuclei of neuroblastoma cells, concentrations of which being significantly higher in nuclei of UKF-NB-4 than in HDFn cells. In HDFn the higher amounts of ellipticine were sequestrated in lysosomes. The extent of ApoElli entering the nuclei in UKF-NB-4 cells was lower than that of free ellipticine and correlated with the formation of ellipticine-derived DNA adducts. Our study indicates that the ApoElli form of ellipticine seems to be a promising tool for neuroblastoma treatment.
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