PMID- 24393721 OWN - NLM STAT- MEDLINE DCOM- 20141124 LR - 20191210 IS - 1464-3391 (Electronic) IS - 0968-0896 (Linking) VI - 22 IP - 2 DP - 2014 Jan 15 TI - Tocopheramine succinate and tocopheryl succinate: mechanism of mitochondrial inhibition and superoxide radical production. PG - 684-91 LID - S0968-0896(13)01044-4 [pii] LID - 10.1016/j.bmc.2013.12.036 [doi] AB - Tocopherols (TOH) are lipophilic antioxidants which require the phenolic OH group for their redox activity. In contrast, non-redox active esters of alpha-TOH with succinate (alpha-TOS) were shown to possess proapoptotic activity in cancer cells. It was suggested that this activity is mediated via mitochondrial inhibition with subsequent O2(-) production triggering apoptosis and that the modification of the linker between the succinate and the lipophilic chroman may modulate this activity. However, the specific mechanism and the influence of the linker are not clear yet on the level of the mitochondrial respiratory chain. Therefore, this study systematically compared the effects of alpha-TOH acetate (alpha-TOA), alpha-TOS and alpha-tocopheramine succinate (alpha-TNS) in cells and submitochondrial particles (SMP). The results showed that not all cancer cell lines are highly sensitive to alpha-TOS and alpha-TNS. In HeLa cells alpha-TNS did more effectively reduce cell viability than alpha-TOS. The complex I activity of SMP was little affected by alpha-TNS and alpha-TOS while the complex II activity was much more inhibited (IC50=42+/-8muM alpha-TOS, 106+/-8muM alpha-TNS, respectively) than by alpha-TOA (IC50 >1000muM). Also the complex III activity was inhibited by alpha-TNS (IC50=137+/-6muM) and alpha-TOS (IC50=315+/-23muM). Oxygen consumption of NADH- or succinate-respiring SMP, involving the whole electron transfer machinery, was dose-dependently decreased by alpha-TOS and alpha-TNS, but only marginal effects were observed in the presence of alpha-TOA. In contrast to the similar inhibition pattern of alpha-TOS and alpha-TNS, only alpha-TOS triggered O2(-) formation in succinate- and NADH-respiring SMP. Inhibitor studies excluded complex I as O2(-) source and suggested an involvement of complex III in O2(-) production. In cancer cells only alpha-TOS was reproducibly able to increase O2(-) levels above the background level but neither alpha-TNS nor alpha-TOA. Furthermore, the stability of alpha-TNS in liver homogenates was significantly lower than that of alpha-TOS. In conclusion, this suggests that alpha-TNS although it has a structure similar to alpha-TOS is not acting via the same mechanism and that for alpha-TOS not only complex II but also complex III interactions are involved. CI - Copyright (c) 2013 Elsevier Ltd. All rights reserved. FAU - Gruber, Julia AU - Gruber J AD - Institute of Pharmacology and Toxicology, Dept. of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria; University of Applied Sciences Wiener Neustadt (FHWN), Wiener Neustadt, Austria. FAU - Staniek, Katrin AU - Staniek K AD - Institute of Pharmacology and Toxicology, Dept. of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria. FAU - Krewenka, Christopher AU - Krewenka C AD - Institute of Medicinal Biochemistry, Dept. of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria. FAU - Moldzio, Rudolf AU - Moldzio R AD - Institute of Medicinal Biochemistry, Dept. of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria. FAU - Patel, Anjan AU - Patel A AD - Dept. of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria. FAU - Bohmdorfer, Stefan AU - Bohmdorfer S AD - Dept. of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria. FAU - Rosenau, Thomas AU - Rosenau T AD - Dept. of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria. FAU - Gille, Lars AU - Gille L AD - Institute of Pharmacology and Toxicology, Dept. of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria. Electronic address: Lars.Gille@vetmeduni.ac.at. LA - eng PT - Journal Article DEP - 20131225 PL - England TA - Bioorg Med Chem JT - Bioorganic & medicinal chemistry JID - 9413298 RN - 0 (Antineoplastic Agents) RN - 0 (Free Radicals) RN - 0 (Succinates) RN - 11062-77-4 (Superoxides) RN - 1406-18-4 (Vitamin E) RN - 7666-00-4 (alpha-tocopheramine) RN - EC 1.3.5.1 (Electron Transport Complex II) RN - EC 7.1.1.2 (Electron Transport Complex I) RN - EC 7.1.1.8 (Electron Transport Complex III) RN - H4N855PNZ1 (alpha-Tocopherol) SB - IM MH - Antineoplastic Agents/chemistry/metabolism/*pharmacology MH - Cell Survival/drug effects MH - Dose-Response Relationship, Drug MH - Drug Screening Assays, Antitumor MH - Electron Transport Complex I/antagonists & inhibitors/metabolism MH - Electron Transport Complex II/antagonists & inhibitors/metabolism MH - Electron Transport Complex III/antagonists & inhibitors/metabolism MH - Free Radicals/metabolism MH - HeLa Cells MH - Humans MH - Mitochondria/*drug effects/metabolism MH - Molecular Structure MH - Structure-Activity Relationship MH - Submitochondrial Particles/drug effects/metabolism MH - Succinates/chemistry/metabolism/*pharmacology MH - Superoxides/*metabolism MH - Tumor Cells, Cultured MH - Vitamin E/*analogs & derivatives/chemistry/metabolism/pharmacology MH - alpha-Tocopherol/chemistry/metabolism/*pharmacology OTO - NOTNLM OT - Electron spin resonance spectroscopy OT - Mitochondria OT - Superoxide radicals OT - Tocopheramine succinate OT - Tocopheryl succinate EDAT- 2014/01/08 06:00 MHDA- 2014/12/15 06:00 CRDT- 2014/01/08 06:00 PHST- 2013/10/30 00:00 [received] PHST- 2013/12/16 00:00 [revised] PHST- 2013/12/16 00:00 [accepted] PHST- 2014/01/08 06:00 [entrez] PHST- 2014/01/08 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] AID - S0968-0896(13)01044-4 [pii] AID - 10.1016/j.bmc.2013.12.036 [doi] PST - ppublish SO - Bioorg Med Chem. 2014 Jan 15;22(2):684-91. doi: 10.1016/j.bmc.2013.12.036. Epub 2013 Dec 25.