Kruspig, Björn*
Dotaz
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Mitochondria play a pivotal role in apoptosis: permeabilization of the outer mitochondrial membrane and the release of pro-apoptotic proteins from the intermembrane space of mitochondria are regarded as the key event in apoptosis induction. Here we demonstrate how non-toxic doses of the mitochondrial Complex II inhibitor thenoyltrifluoroacetone (TTFA), which specifically inhibits the ubiquinone-binding site of succinate dehydrogenase (SDH), synergistically stimulated cell death, induced by harmless doses of cisplatin in a panel of chemoresistant neuroblastoma cell lines. Apoptotic cell death was confirmed by cytochrome c release from the mitochondria, cleavage of poly ADP-ribose polymerase, processing of caspase-3, which is an important executive enzyme in apoptosis, and caspase-3-like activity. Methyl malonate, an inhibitor of the SDHA subunit partially reversed apoptosis stimulated by TTFA in SK-N-BE(2) neuroblastoma cells (NB), indicating that sensitization requires oxidation of succinate. In contrast, in IMR-32 NB cells, the same concentrations of TTFA markedly suppressed cisplatin-induced apoptosis. Comparison of oxygen consumption in cisplatin-resistant SK-N-BE(2) and cisplatin-sensitive IMR-32 cells clearly demonstrated impaired Complex II activity in IMR-32 cells. We also found that in SK-N-BE(2) cells co-treatment with cisplatin and TTFA markedly stimulated formation of reactive oxygen species (ROS), whereas in IMR cells, cisplatin-mediated ROS production was attenuated by TTFA, which explains apoptosis suppression in these cells. Thus, functionally active SDH is a prerequisite for the ROS-mediated sensitization to treatment by TTFA.
- MeSH
- apoptóza účinky léků MeSH
- chemorezistence MeSH
- cílená molekulární terapie * MeSH
- cisplatina farmakologie MeSH
- kyselina jantarová metabolismus MeSH
- lidé MeSH
- mitochondrie účinky léků enzymologie MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny antagonisté a inhibitory MeSH
- neuroblastom patologie MeSH
- oxidace-redukce MeSH
- protinádorové látky farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- respirační komplex II antagonisté a inhibitory MeSH
- screeningové testy protinádorových léčiv MeSH
- spotřeba kyslíku účinky léků MeSH
- superoxidy metabolismus MeSH
- synergismus léků MeSH
- thenoyltrifluoraceton farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
