Abstract
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 (IDHmut GSCs) resulted in a paucity of preclinical models in IDHmut glioma, limiting the discovery of new effective chemotherapeutic agents. To fill this gap, we used six recently developed patient-derived IDHmut 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 IDHmut 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 (IC50) below 1 µM and maximum inhibitory effects (Emax) below 25%. These findings were validated in an additional four IDHmut 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 IC50 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 IDHmut gliomas.
Highlights
The differentiation of glioma patients into isocitrate dehydrogenase (IDH) mutant and wildtype tumors (IDHmut /IDHwt ) has proven to be a solid prognostic marker of patient outcome [1]
One reason for uncertainty is the paucity of preclinical models in IDHmut glioma, which has hindered the development of innovative therapies
In order to identify novel and effective antineoplastic drugs for the treatment of IDHmut glioma, we performed a high-throughput screening, utilizing a drug library consisting of 147 drugs approved by the Food and Drug Administration (FDA) for the treatment of different cancer types
Summary
The differentiation of glioma patients into isocitrate dehydrogenase (IDH) mutant and wildtype tumors (IDHmut /IDHwt ) has proven to be a solid prognostic marker of patient outcome [1]. Patients harboring an IDH mutation fare much better than patients without [2]. Treatment consensus exists in IDHwt glioma, such as glioblastoma (GBM), and comprises maximal safe resection, Cells 2020, 9, 1389; doi:10.3390/cells9061389 www.mdpi.com/journal/cells. In IDHmut lower grade glioma (LGG), the current standard is surgical resection, followed by procarbazine, lomustine, and vincristine (PCV) or temozolomide combined with radiation therapy. While IDHwt glioma cell models have shown easy expansion and maintenance, difficulties in cultivating IDHmut tumor cells have forced many to introduce the IDH mutation artificially into wildtype tumor cells, not accounting for the natural genetic background of the tumor [9,10]
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