High cytotoxicity of cisplatin nanocapsules in ovarian carcinoma cells depends on uptake by caveolae-mediated endocytosis
| Autor: | Rutger W.H.M. Staffhorst, Paul M.P. van Bergen en Henegouwen, Jan Reedijk, Irene H.L. Hamelers, Anton I.P.M. de Kroon, Ben de Kruijff, Jarno Voortman |
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| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Endosome Cell Caveolin 1 Antineoplastic Agents Biology Endocytosis Caveolae Nanocapsules Cell Line Tumor medicine Humans Cytotoxicity Platinum Cisplatin Ovarian Neoplasms Biological Transport medicine.anatomical_structure Cell killing Oncology Immunology Biophysics Female Intracellular medicine.drug |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 15(4) |
| ISSN: | 1078-0432 |
| Popis: | Purpose: Cisplatin nanocapsules, nanoprecipitates of cisplatin encapsulated in phospholipid bilayers, exhibit increased in vitro toxicity compared with the free drug toward a panel of human ovarian carcinoma cell lines. To elucidate the mechanism of cell killing by nanocapsules and to understand the cell line dependence of nanocapsule efficacy, the route of uptake and the intracellular fate of the nanocapsules were investigated.Experimental Design: Intracellular platinum accumulation and cisplatin-DNA-adduct formation were measured in cell lines that differ in sensitivity to cisplatin nanocapsules. Confocal fluorescence microscopy in combination with down-regulation with small interfering RNA was used to map the route of cellular uptake of nanocapsules containing fluorescein-labeled cisplatin.Results: In sensitive cell lines, cisplatin from nanocapsules is taken up much more efficiently than the free compound. In IGROV-1 cells, the increased platinum accumulation results in augmented cisplatin-DNA-adduct formation. Confocal fluorescence microscopy revealed that the uptake of nanocapsules is energy dependent. Colocalization with markers of early and late endosomes indicated uptake via endocytosis. Down-regulation of caveolin-1 with small interfering RNA inhibited the uptake and cytotoxic effect of nanocapsules in IGROV-1 cells. Ovarian carcinoma cells, in which the nanocapsules are less effective than in IGROV-1 cells, do not internalize the nanocapsules (OVCAR-3) or accumulate them in an endocytic compartment after clathrin-mediated endocytosis (A2780).Conclusions: The high cytotoxicity of cisplatin nanocapsules requires caveolin-1-dependent endocytosis that is followed by release of the drug from a late endosomal/lysosomal compartment and cisplatin-DNA-adduct formation. The findings may be applied in predicting the efficacy of nanoparticulate anticancer drug delivery systems in treating different tumor types. |
| Databáze: | OpenAIRE |
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