Publication details

Potlačení rezistence buněk neuroblastomu na cílenou nádorovou terapii založenou na inhibici kinázy Akt

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Title in English Overcoming neuroblastoma resistance to targeted Akt-kinase inhibition based therapy
Authors

NAVRÁTILOVÁ Jarmila BUDKOVÁ Zuzana JIRÁKOVÁ Ludmila KARASOVÁ Martina DLABKOVÁ Kristýna PREISLER Jan ŠMARDA Jan

Year of publication 2015
Type Appeared in Conference without Proceedings
MU Faculty or unit

Faculty of Science

Citation
Description Glucose dependency of tumor cells for ATP supply and reactive species deactivation is well known and already clinically used for the detection of malignant tumors (FDG-PET). Deregulated activation of the anti-apoptotic signaling pathways (PI3K/Akt/mTOR, MAPK) is another important marker of malignant transformation. Neuroblastoma is malignant childhood cancer derived from primitive neural crest cells. It is extracranial solid tumor. Constitutive expression of the active anti-apoptotic Akt kinase is frequently detected in neuroblastoma cells and correlates well with metastatic potencial. Both glucose uptake and Akt kinase inhibitors have been evaluated in the early stage clinical trials. Tumor cells including neuroblastoma show great adaptability to chemotherapy. PI3K/Akt pathway inhibition results in the compensatory activation of HER receptors and ERK signaling pathway. Similarly, glucose uptake inhibition is associated with AMPK kinase activation and mitochondrial biogenesis. The goal of this study is to describe the molecular mechanisms of tumor cells determining their resistence to Akt kinase and glucose uptake inhibitors. We show that both Akt kinase and glucose uptake inhibition does not restrict the number of viable neuroblastoma cells. The possible explanation is the activation of the compensatory mitochondrial metabolism in these cells. In addition, we propose the pharmacological inhibition of this mitochondrial compensatory pathways (MIBG, tetrathiomolybdate, rotenone) for synergistic increase of Akt kinase inhibitors cytotoxicity.
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