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Large-Scale Drug Screening in Patient-Derived IDH<sup>mut</sup> Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents
oleh: Philip Dao Trong, Gerhard Jungwirth, Tao Yu, Stefan Pusch, Andreas Unterberg, Christel Herold-Mende, Rolf Warta
| Format: | Article |
|---|---|
| Diterbitkan: | MDPI AG 2020-06-01 |
Deskripsi
The discovery of the isocitrate dehydrogenase (IDH) mutation in glioma led to a paradigm shift on how we see glioma biology. Difficulties in cultivating IDH mutant glioma stem cells (IDH<sup>mut</sup> GSCs) resulted in a paucity of preclinical models in IDH<sup>mut</sup> glioma, limiting the discovery of new effective chemotherapeutic agents. To fill this gap, we used six recently developed patient-derived IDH<sup>mut</sup> GSC lines and performed a large-scale drug screening with 147 Food and Drug Administration (FDA)-approved anticancer drugs. GSCs were subjected to the test compounds for 72 h in concentrations ranging from 0.0001 to 1 µM. Cell viability was assessed by CellTiterGlo and the induction of apoptosis by flow cytometry with Annexin V/propidium iodide staining. The initial screen was performed with two IDH<sup>mut</sup> GSC lines and identified seven drugs (bortezomib, carfilzomib, daunorubicin, doxorubicin, epirubicin, omacetaxine, plicamycin) with a substantial antiproliferative activity, as reflected by half maximal inhibitory concentrations (IC<sub>50</sub>) below 1 µM and maximum inhibitory effects (E<sub>max</sub>) below 25%. These findings were validated in an additional four IDH<sup>mut</sup> GSC lines. The candidate drugs, of which plicamycin and omacetaxine are known to cross the blood brain barrier, were used for subsequent cell death analyses. A significant induction of apoptosis was observed at IC<sub>50</sub> values of the respective drugs. In summary, we were able to identify seven FDA-approved drugs that should be further taken into clinical investigations for the treatment of IDH<sup>mut</sup> gliomas.