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

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.

Precise nano-system-based drug delivery and synergistic therapy against androgen receptor-positive triple-negative breast cancer

“…S1 ). We refer to the high-throughput drug combination screening method and introduce the Sensitivity index (SI) score to evaluate the impact of synergies 31 . The SI score refers to the difference between the predicted and actual combined effects.…”

“…2 B), indicating that enzalutamide and MK-8776 interacted in a synergistic manner. Moreover, we employed typical synergy models (HSA and Bliss) to estimate the HSA and Bliss values, which are a readout for synergistic inhibition and show the discrepancy between expected and observed inhibition 31 , 34 . The majority of the HSA and Bliss values exceeded 0, showing that the two drugs interacted synergistically ( Fig.…”

Advances in computational and translational approaches for malignant glioma

“…In this study, they subject patient-derived BTICs to a migration assay using a microfluidic device and show that quantitative measurement of in vitro migration as well as proliferation capacity can be used to predict progression-free survival with 86% accuracy in a retrospective cohort of 28 patients ( Wong et al, 2021 ). Other groups have also developed microfluidic, tumor-on-a-chip systems to interrogate drug efficacy as well as novel drug delivery approaches including nanoparticle-based therapies ( Fan et al, 2016 ; Xiao et al, 2019 ; Chen et al, 2020 ; Liu et al, 2021 ). The latter employs techniques such as surface plasmon resonance that can assess target-specificity and binding interactions ( Schneider et al, 2015 ; Bhargav et al, 2020 ).…”

The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products

“…This concept was supported by several reports as follows. TH588 (a MutT homolog 1 (MTH1) inhibitor) and BKM120 (a pan-PI3K inhibitor) combined treatment promotes DNA damage and apoptosis by activating PI3K/AKT/mTOR in glioma cells [ 189 ]. Various PI3K isoforms differentially regulate the cell cycle, DNA replication, and DNA damage repair [ 190 ].…”