High-Dose Compound Heat Map for 3D-Cultured Glioblastoma Multiforme Cells in a Micropillar and Microwell Chip Platform.

Dong Woo Lee,Sang-Yun Lee,Gyu Ha Ryu,Il Doh,Do-Hyun Nam

doi:10.1155/2017/7218707

Abstract

Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. To cure GBM patients, many target-specific chemotherapeutic agents have been developing. However, 2D monolayer cell-based toxicity and efficacy tests did not efficiently screen agents due to the pool reflection of in vivo microenvironments (cell-to-cell and cell-to-extracellular matrix interaction). In this study, we used a 3D cell-based, high-throughput screening method reflecting the microenvironments using a micropillar and microwell chip platform to draw a high-dose heat map of the cytotoxicity and efficacy of 70 compounds, with two DMSO controls. Moreover, the high-dose heat map model compared the responses of four 3D-cultured patient-derived GBM cells and astrocytes to high dosages of compounds with respect to efficacy and cytotoxicity, respectively, to discern the most efficacious drug for GBM. Among the 70 compounds tested, cediranib (a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases) exhibited the lowest cytotoxicity to astrocytes and high efficacy to GBM cells in a high-dose heat map model.

Highlights

Glioblastoma multiforme (GBM) is the most common, aggressive, and lethal primary malignant brain tumor that stems from astrocytes
The current standard of care is surgical resection coupled with ionizing radiation (IR) and the chemotherapeutic agent temozolomide (Temodar5, Temodal5, TMZ) [2, 3]
We evaluated cytotoxicity of other compounds in comparison to TMZ and evaluated the efficacy of these compounds with patient-derived GBM cells

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common, aggressive, and lethal primary malignant brain tumor that stems from astrocytes. The current standard of care is surgical resection coupled with ionizing radiation (IR) and the chemotherapeutic agent temozolomide (Temodar, Temodal, TMZ) [2, 3] This treatment only provides patients with GBM a 12–14-month survival period after diagnosis [2, 3]. Previous high-dose heat map models using 2D cell-based high-throughput screening are well developed [9, 10]. Assay based on 3D cultured astrocyte and GBMs with high-throughput manner may give new potential to screen GBM target agents. Since TMZ is a representative drug used in the treatment of patients with GBM, it was used as a control compound to verify the high-dose heat map. By comparing TMZ with 69 other compounds, compounds in the high-dose heat map were tested for cytotoxicity and efficacy in GBM cells

Materials and Methods

Results and Discussion

Conclusion