Distinct effects of etoposide on glutamine-addicted neuroblastoma
| Autor: | Kadri Valter, Alibek Abdrakhmanov, Boris Zhivotovsky, Vladimir Gogvadze, Polina Maximchik, Viacheslav V Senichkin |
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| Rok vydání: | 2018 |
| Předmět: |
Glutamine
Respiratory chain Apoptosis Mitochondrion Cellular and Molecular Neuroscience chemistry.chemical_compound Neuroblastoma Oxygen Consumption Cell Line Tumor Humans Mitochondrial respiratory chain complex I Inner mitochondrial membrane Molecular Biology Etoposide Pharmacology biology Chemistry Cytochrome c Cell Biology Glutathione Antineoplastic Agents Phytogenic Cell biology Mitochondria Oxidative Stress biology.protein Molecular Medicine Original Article |
| Zdroj: | Cellular and Molecular Life Sciences |
| ISSN: | 1420-9071 |
| Popis: | The majority of anticancer drugs are DNA-damaging agents, and whether or not they may directly target mitochondria remains unclear. In addition, tumors such as neuroblastoma exhibit addiction to glutamine in spite of it being a nonessential amino acid. Our aim was to evaluate the direct effect of widely used anticancer drugs on mitochondrial activity in combination with glutamine withdrawal, and possible apoptotic effects of such interaction. Our results revealed that etoposide inhibits mitochondrial respiratory chain Complex I causing the leakage of electrons and the superoxide radical formation. However, it was not sufficient to induce apoptosis, and apoptotic manifestation was detectable only alongside the withdrawal of glutamine, a precursor for antioxidant glutathione. Thus, the simultaneous depletion of glutathione and destabilization of mitochondria by ROS can compromise the barrier properties of the mitochondrial membrane, leading to cytochrome c release and the activation of the mitochondrial apoptotic pathway. Thus, the depletion of antioxidants or the inhibition of the pathways responsible for cellular antioxidant response can enhance mitochondrial targeting and strengthen antitumor therapy. Electronic supplementary material The online version of this article (10.1007/s00018-019-03232-z) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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