DDIS-34. HIGH-THROUGHPUT DRUG SCREENING OF FDA-APPROVED ANTINEOPLASTIC DRUGS FOR THE TREATMENT OF AGGRESSIVE MENINGIOMAS

摘要

Currently, we are facing several challenges in the treatment of meningiomas: only subtotally removable tumors, high rate of recurrence in higher-grade meningiomas, malignancy, and lack of effective chemotherapeutic agents for aggressive or inoperable tumors. For these reasons, there is an urgent need for more successful treatments for aggressive meningiomas. Therefore, we used 147 FDA-approved antineoplastic drugs on two different meningioma cell lines, including the genetically modified cell line Ben-Men-1 (WHO°I) and the newly established anaplastic meningioma cell line NCH93 (WHO°III). The impact of the drugs on proliferation was assessed in a high-throughput 386-well format with CellTiter-Glo (Promega) and further validation was done by crystal-violet assay. Subsequent screening of 147 FDA-approved drugs resulted in the identification of potential 5 drugs, including Bortezomib, Carfilzomib, Omacetaxine, Paclitaxel, and Ponatinib. Dose-curve analysis revealed IC50 values of these drugs in the Ben-Men-1 and NCH93 cell lines as follows: Bortezomib 16.2 and 5.7 nM, Carfilzomib 4.8 and 2.6 nM, Omacetaxine and 5.0 and 8.9 nM, Paclitaxel 2.6 and 1.9 µM, and Ponatinib 278 and 206 nM. Inhibitor dosage of 10xIC50 values and higher lead to an average inhibition of Ben-Men-1 and NCH93 cells by up to 90% on day 2 (P< .001). The impact of the antineoplastic agents on the cell cycle was analyzed by flow cytometry. Percentages of sub-G1 phase were significantly elevated with increasing drug concentrations of all five tested compounds (P< .001). To assess the effects of the drugs on migration scratch assay was performed. Drug concentrations of 10xIC50 values resulted in an inhibition of migration in Ben-Men-1 cells for Bortezomib, Carfilzomib, and Omacetaxine by 49%, 30%, and 23%, respectively (P< .05). In conclusion, we identified 5 promising drugs for the treatment of aggressive meningiomas by applying a high-throughput drug screening of 147 FDA-approved antineoplastic drugs.