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Keywords {🔍}

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Topics {✒️}

1h-indol-3-yl] butan-1-yl]spiro[isobenzofuran-1 heat-induced epitope retrieval article download pdf anti-human specific cd56 patient-derived spheroid cultures preserves anti-mir stability n-methyl-d-aspartate patient-derived spheroids cultures anti-cancer agent siramesine nmda-induced cell death charlotte aaberg-jessen & bjarne siramesine-induced cell death extra-lysosomal proteolytic systems patient-derived spheroids exposed efficient target de-repression confocal time-lapse imaging newborn wistar rats pronounced anti-migratory effect full access related subjects ��7 inhibitor z-devd-fmk spheroid-brain slice blood–brain-barrier dmso corticostriatal slice cultures fetal brain tissue compromised/ruptured lysosomal membranes cell death pathway anti-human cd56 brain slice cultures secondary spheroids formation privacy choices/manage cookies assessed students t-test glioblastoma stem cell patient-derived spheroids glioma cell migration anti-cancer drug [9] cells expressing neuronal tumor-initiating stem glioblastoma cell lines glioma cell lines blood–brain-barrier blood–brain barrier human glioma tissue stem cell markers induce cell death creative commons license adherent cell lines confocal z-stacks brain drug development resistant tumor stem

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         headline:Effects of the lysosomal destabilizing drug siramesine on glioblastoma in vitro and in vivo
         description:Glioblastoma is the most frequent and most malignant brain tumor with the patients having a median survival of only 14.6 months. Although glioblastoma patients are treated with surgery, radiation and chemotherapy recurrence is inevitable. A stem-like population of radio- and chemoresistant brain tumor-initiating cells combined with the invasive properties of the tumors is believed to be critical for treatment resistance. In the present study, the aim was to investigate the effect of a novel therapeutic strategy using the lysosomotropic detergent siramesine on glioblastomas. Standard glioma cell lines and patient-derived spheroids cultures with tumor-initiating stem-like cells were used to investigate effects of siramesine on proliferation and cell death. Responsible mechanisms were investigated by inhibitors of caspases and cathepsins. Effects of siramesine on migrating tumor cells were investigated by a flat surface migration assay and by implanting spheroids into organotypic rat brain slice cultures followed by confocal time-lapse imaging. Finally the effect of siramesine was investigated in an orthotopic mouse glioblastoma model. Results obtained in vitro and in vivo were confirmed by immunohistochemical staining of histological sections of spheroids, spheroids in brain slice cultures and tumors in mice brains. The results showed that siramesine killed standard glioma cell lines in vitro, and loss of acridine orange staining suggested a compromised lysosomal membrane. Co-treatment of the cell lines with inhibitors of caspases and cathepsins suggested differential involvement in cell death. Siramesine caused tumor cell death and reduced secondary spheroid formation of patient-derived spheroid cultures. In the flat surface migration model siramesine caused tumor cell death and inhibited tumor cell migration. This could not be reproduced in the organotypic three dimensional spheroid-brain slice culture model or in the mice xenograft model. In conclusion the in vitro results obtained with tumor cells and spheroids suggest a potential of lysosomal destabilizing drugs in killing glioblastoma cells, but siramesine was without effect in the organotypic spheroid-brain slice culture model and the in vivo xenograft model.
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      headline:Effects of the lysosomal destabilizing drug siramesine on glioblastoma in vitro and in vivo
      description:Glioblastoma is the most frequent and most malignant brain tumor with the patients having a median survival of only 14.6 months. Although glioblastoma patients are treated with surgery, radiation and chemotherapy recurrence is inevitable. A stem-like population of radio- and chemoresistant brain tumor-initiating cells combined with the invasive properties of the tumors is believed to be critical for treatment resistance. In the present study, the aim was to investigate the effect of a novel therapeutic strategy using the lysosomotropic detergent siramesine on glioblastomas. Standard glioma cell lines and patient-derived spheroids cultures with tumor-initiating stem-like cells were used to investigate effects of siramesine on proliferation and cell death. Responsible mechanisms were investigated by inhibitors of caspases and cathepsins. Effects of siramesine on migrating tumor cells were investigated by a flat surface migration assay and by implanting spheroids into organotypic rat brain slice cultures followed by confocal time-lapse imaging. Finally the effect of siramesine was investigated in an orthotopic mouse glioblastoma model. Results obtained in vitro and in vivo were confirmed by immunohistochemical staining of histological sections of spheroids, spheroids in brain slice cultures and tumors in mice brains. The results showed that siramesine killed standard glioma cell lines in vitro, and loss of acridine orange staining suggested a compromised lysosomal membrane. Co-treatment of the cell lines with inhibitors of caspases and cathepsins suggested differential involvement in cell death. Siramesine caused tumor cell death and reduced secondary spheroid formation of patient-derived spheroid cultures. In the flat surface migration model siramesine caused tumor cell death and inhibited tumor cell migration. This could not be reproduced in the organotypic three dimensional spheroid-brain slice culture model or in the mice xenograft model. In conclusion the in vitro results obtained with tumor cells and spheroids suggest a potential of lysosomal destabilizing drugs in killing glioblastoma cells, but siramesine was without effect in the organotypic spheroid-brain slice culture model and the in vivo xenograft model.
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      dateModified:2017-03-07T00:00:00Z
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         Siramesine
         Glioblastoma
         Cancer stem cell
         Lysosomes
         Spheroids
         Brain slice cultures
         Cancer Research
         Oncology
         Surgical Oncology
         Health Promotion and Disease Prevention
         Biomedicine
         general
         Medicine/Public Health
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      name:Institute of Clinical Research, University of Southern Denmark, Odense C, Denmark
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