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Cancer Cell International
Published in: Cancer Cell International 1/2020

01-12-2020 | Glioblastoma | Primary research

A high-throughput drug combination screen identifies an anti-glioma synergism between TH588 and PI3K inhibitors

Authors: Zhen Chen, Chao Chen, Tingting Zhou, Chao Duan, Qianqian Wang, Xiaohui Zhou, Xia Zhang, Fangrong Wu, Yunfen Hua, Fan Lin

Published in: Cancer Cell International | Issue 1/2020

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Abstract

Background

Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor. More than half of GBMs contain mutation(s) of PTEN/PI3K/AKT, making inhibitors targeting the PI3K pathway very attractive for clinical investigation. However, so far, PI3K/AKT/mTOR inhibitors have not achieved satisfactory therapeutic effects in clinical trials of GBM. In this study, we aimed to develop a high-throughput screening method for high-throughput identification of potential targeted agents that synergize with PI3K inhibitors in GBM.

Methods

A Sensitivity Index (SI)-based drug combination screening method was established to evaluate the interactions between BKM120, a pan-PI3K inhibitor, and compounds from a library of 606 target-selective inhibitors. Proliferation, colony and 3D spheroid formation assays, western blotting, comet assay, γ-H2AX staining were used to evaluate the anti-glioma effects of the top-ranked candidates. The drug combination effects were analyzed by the Chou-Talalay method.

Results

Six compounds were successfully identified from the drug screen, including three previously reported compounds that cause synergistic antitumor effects with PI3K/mTOR inhibitors. TH588, an putative MTH1 inhibitor exhibited significant synergy with BKM120 in suppressing the proliferation, colony formation and 3D spheroid formation of GBM cells. Further investigation revealed that both DNA damage and apoptosis were markedly enhanced upon combination treatment with TH588 and BKM120. Finally, activation of PI3K or overexpression of AKT compromised the anti-glioma efficacy of TH588.

Conclusions

The screening method developed in this study demonstrated its usefulness in the rapid identification of synergistic drug combinations of PI3K inhibitors and targeted agents.
Appendix
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Metadata
Title
A high-throughput drug combination screen identifies an anti-glioma synergism between TH588 and PI3K inhibitors
Authors
Zhen Chen
Chao Chen
Tingting Zhou
Chao Duan
Qianqian Wang
Xiaohui Zhou
Xia Zhang
Fangrong Wu
Yunfen Hua
Fan Lin
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01427-0

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