Targeting succinate: ubiquinone reductase potentiates the efficacy of anticancer therapy

Kruspig, B., Valter, K., Skender, B., Zhivotovsky, B. and Gogvadze, V. (2016) Targeting succinate: ubiquinone reductase potentiates the efficacy of anticancer therapy. Biochimica et Biophysica Acta: Molecular Cell Research, 1863(8), pp. 2065-2071. (doi: 10.1016/j.bbamcr.2016.04.026) (PMID:27140478)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kruspig, Dr Bjorn
• Authors: Kruspig, B., Valter, K., Skender, B., Zhivotovsky, B., and Gogvadze, V.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Biochimica et Biophysica Acta: Molecular Cell Research
• Publisher: Elsevier
• ISSN: 0167-4889
• ISSN (Online): 0167-4889
• Published Online: 29 April 2016