Large-Scale Drug Screening in Patient-Derived IDH<sup>mut</sup> Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents
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> glio...
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MDPI AG
2020-06-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/6/1389 |
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| author | Philip Dao Trong Gerhard Jungwirth Tao Yu Stefan Pusch Andreas Unterberg Christel Herold-Mende Rolf Warta |
| author_facet | Philip Dao Trong Gerhard Jungwirth Tao Yu Stefan Pusch Andreas Unterberg Christel Herold-Mende Rolf Warta |
| author_sort | Philip Dao Trong |
| collection | DOAJ |
| description | 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. |
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| language | English |
| last_indexed | 2024-03-10T19:23:25Z |
| publishDate | 2020-06-01 |
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| series | Cells |
| spelling | doaj.art-02fa7134a249469982be048ed9009afc2023-11-20T02:43:54ZengMDPI AGCells2073-44092020-06-0196138910.3390/cells9061389Large-Scale Drug Screening in Patient-Derived IDH<sup>mut</sup> Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic AgentsPhilip Dao Trong0Gerhard Jungwirth1Tao Yu2Stefan Pusch3Andreas Unterberg4Christel Herold-Mende5Rolf Warta6Department of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69120 Heidelberg, GermanyDepartment of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Neurosurgery, Division of Experimental Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, GermanyThe 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.https://www.mdpi.com/2073-4409/9/6/1389drug screenlower grade gliomaisocitrate dehydrogenase (IDH) mutant glioma stem cellsbortezomibcarfilzomibdaunorubicin |
| spellingShingle | Philip Dao Trong Gerhard Jungwirth Tao Yu Stefan Pusch Andreas Unterberg Christel Herold-Mende Rolf Warta Large-Scale Drug Screening in Patient-Derived IDH<sup>mut</sup> Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents Cells drug screen lower grade glioma isocitrate dehydrogenase (IDH) mutant glioma stem cells bortezomib carfilzomib daunorubicin |
| title | Large-Scale Drug Screening in Patient-Derived IDH<sup>mut</sup> Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents |
| title_full | Large-Scale Drug Screening in Patient-Derived IDH<sup>mut</sup> Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents |
| title_fullStr | Large-Scale Drug Screening in Patient-Derived IDH<sup>mut</sup> Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents |
| title_full_unstemmed | Large-Scale Drug Screening in Patient-Derived IDH<sup>mut</sup> Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents |
| title_short | Large-Scale Drug Screening in Patient-Derived IDH<sup>mut</sup> Glioma Stem Cells Identifies Several Efficient Drugs among FDA-Approved Antineoplastic Agents |
| title_sort | large scale drug screening in patient derived idh sup mut sup glioma stem cells identifies several efficient drugs among fda approved antineoplastic agents |
| topic | drug screen lower grade glioma isocitrate dehydrogenase (IDH) mutant glioma stem cells bortezomib carfilzomib daunorubicin |
| url | https://www.mdpi.com/2073-4409/9/6/1389 |
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