Dual targeting of mitochondrial function and mTOR pathway as a therapeutic strategy for diffuse intrinsic pontine glioma

Oncotarget
Maria TsoliDavid S Ziegler

Abstract

Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways. The mitochondrion is an attractive target as a key organelle that facilitates these critical processes. PENAO is a novel anti-cancer compound that targets mitochondrial function by inhibiting adenine nucleotide translocase (ANT). Here we found that DIPG neurosphere cultures express high levels of ANT2 protein and are sensitive to the mitochondrial inhibitor PENAO through oxidative stress, while its apoptotic effects were found to be further enhanced upon co-treatment with mTOR inhibitor temsirolimus. This combination therapy was found to act through inhibition of PI3K/AKT/mTOR pathway, HSP90 and activation of AMPK.In vivoexperiments employing an orthotopic model of DIPG showed a marginal anti-tumour effect likely due to poor...Continue Reading

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Citations

Nov 30, 2018·International Journal of Molecular Sciences·Cristina Trejo-SolísJulio Sotelo
Jul 23, 2019·Proteomics·Ryan J DuchatelMatthew D Dun
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Nov 5, 2021·Acta Neuropathologica Communications·Cheng XuHai Yan

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Methods Mentioned

BETA
FACS
Flowcytometric
profiler
xenograft
xenografts
fluorescence activated cell sorting
PCR
Protein

Software Mentioned

GraphPad Prism
FACS
CalcuSyn

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