Selective Death of Y79 Retinoblastoma Cells by Magnetic Hyperthermia via Caspase Dependent Apoptotic Pathway

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Investigative Ophthalmology & Visual Science


Purpose : To evaluate the selective death of Y79 retinoblastoma cells using dextran-coated iron oxide nanoparticles in a magnetic hyperthermia paradigm and assess the molecular pathways that play a role in cell death.

Methods : Y79 and ARPE-19 cells were exposed to different concentrations of dextran-coated iron oxide magnetic nanoparticles: 250, 500, 750 and 1000 µg/ml. After 2 hours of incubation, cells were exposed to a magnetic field with frequency and intensity values of 250 kHz and 4 kA/m at temperature of 43-44 degreeC for 30 minutes. Hyperthermia induced apoptosis was assessed at 4, 24 and 72 hours after treatment. Transmission electron microscopy was performed to elucidate the cellular uptake and distribution of nanoparticles in Y79 and ARPE-19 cells. Gene expression profiling for apoptosis was performed using RT2 Profiler PCR arrays.

Results : At 4 hours, cell death for Y79 cells was estimated to be 16, 16, 18 and 24% for 250, 500, 750 and 1000 µg/ml, respectively. At 24 hours, cell death in Y79 cells was estimated to be 46, 57, 67, and 73% at respective four concentrations. Y79 retinoblastoma cells underwent apoptosis at 72 hours with cell death estimated at 16, 48, 52 and 57% respectively with increasing nanoparticle concentrations. Magnetic hyperthermia did not have a significant toxic effect on ARPE-19 cells for all four concentrations of nanoparticles. Minimal baseline cytotoxicity of nanoparticles was observed without magnetic field activation. Transmission Electron Microscopy images showed that dextran-coated iron oxide nanoparticles were engulfed into the cytoplasm of both Y79 and ARPE-19 cells and specifically located in endosomes. Gene expression profiling showed that genes in the FAS signaling pathway and TNF alpha signaling were activated in Y79 retinoblastoma cells at 24 hours after magnetic hyperthermia. qRT-PCR results showed an increased gene expression of caspase8, caspase10, caspase14, caspase9 and cytochromeC. 48 hours after magnetic hyperthermia, we observed significantly increased caspase 3/7 activity in Y79 cells, confirming that apoptosis through intrinsic and extrinsic pathways were activated in these cells.

Conclusions : Magnetic hyperthermia using dextran-coated iron oxide nanoparticles were engulfed by both Y79 and ARPE-19 cells. They satisfactorily and selectively killed Y79 cells at 750 and 1000 µg/ml concentrations via activation of two apoptotic pathways.






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