Abstract
The management of aggressive meningiomas remains challenging due to limited treatment options besides surgical removal and radiotherapy. High recurrence rates and lack of effective chemotherapies may be reasons for the unfavorable prognosis of these patients. Consequently, there is an urgent need to identify effective therapeutic agents. For this purpose, we performed a high-throughput screening utilizing a drug library consisting of 147 FDA-approved antineoplastic drugs on the anaplastic meningioma cell line NCH93 using CellTiter-Glo (Promega). Based on the lowest IC50, the top 5 drugs were selected including Bortezomib, Carfilzomib, Omacetaxine, Ixabepilone, and Romidepsin. Validation of candidate compounds was performed in Ben-Men-1 (grade I), NCH93 (grade III), and IOMM-Lee cells (grade III) using crystal violet assay. Dose-curve analysis revealed IC50 values in the lower nanomolar range for all compounds and all cell lines (0.2 – 16.2 nM). To further substantiate our findings, cell proliferation assessed by manual counting was significantly reduced by up to 90% by each candidate drug at 10xIC50 after 48 h (P < 0.001). Furthermore, cell migration was inhibited up to 60% by all candidate drugs at the respective IC50 (P < 0.05). However, colony formation was only significantly reduced by Bortezomib and Carfilzomib (P < 0.001). The impact of the drugs on cell cycle and apoptosis was analyzed by flow cytometry using Annexin V/PI staining. All candidate drugs induced cell cycle arrest at G0/G1 or G2/M phase (P < 0.001) and subsequently induced apoptosis. Among them, Bortezomib exhibited the most pronounced effect by up to 80% of apoptotic cells (P < 0.001). In summary, by utilizing a high-throughput drug screening we were able to identify Bortezomib, Carfilzomib, Omacetaxine, Ixabepilone, and Romidepsin as potent antineoplastic agents for the treatment of aggressive meningiomas.