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Mitochondrial targeting of alpha-tocopheryl succinate enhances its anti-mesothelioma efficacy
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SYSNO ASEP 0431276 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Mitochondrial targeting of alpha-tocopheryl succinate enhances its anti-mesothelioma efficacy Author(s) Kovářová, Jaromíra (BTO-N) RID
Bajziková, Martina (BTO-N) RID
Vondrusová, Magdaléna (BTO-N) RID
Štursa, Jan (UOCHB-X)
Goodwin, J. (AU)
Nguyen, M. (AU)
Zobalová, Renata (BTO-N) RID
Pesdar, E.A. (AU)
Truksa, Jaroslav (BTO-N) RID, ORCID
Tomasetti, M. (IT)
Dong, L. F. (AU)
Neužil, Jiří (BTO-N) RIDSource Title Redox Report. - : Taylor & Francis - ISSN 1351-0002
Roč. 19, č. 1 (2014), s. 16-25Number of pages 10 s. Language eng - English Country GB - United Kingdom Keywords Vitamin E analogues ; Mitochondrial targeting ; Reactive oxygen species Subject RIV EB - Genetics ; Molecular Biology R&D Projects GAP301/10/1937 GA ČR - Czech Science Foundation (CSF) GAP305/12/1708 GA ČR - Czech Science Foundation (CSF) Institutional support BTO-N - RVO:86652036 ; UOCHB-X - RVO:61388963 UT WOS 000337129600003 DOI 10.1179/1351000213Y.0000000064 Annotation Malignant mesothelioma (MM) is a fatal neoplastic disease with no therapeutic option. Therefore, the search for novel therapies is of paramount importance. Methods: Since mitochondrial targeting of alpha-tocopheryl succinate (alpha-TOS) by its tagging with triphenylphosphonium enhances its cytotoxic effects to cancer cells, we tested its effect on MM cells and experimental mesotheliomas. Results: Mitochondrially targeted vitamin E succinate (MitoVES) was more efficient in killing MM cells than a-TOS with IC50 lower by up to two orders of magnitude. Mitochondrial association of MitoVES in MM cells was documented using its fluorescently tagged analogue. MitoVES caused apoptosis in MM cells by mitochondrial destabilization, resulting in the loss of mitochondrial membrane potential, generation of reactive oxygen species, and destabilization of respiratory supercomplexes. The role of the mitochondrial complex II in the activity of MitoVES was confirmed by the finding that MM cells with suppressed succinate quinone reductase were resistant to MitoVES. MitoVES suppressed mesothelioma growth in nude mice with high efficacy. Discussion: MitoVES is more efficient in killing MM cells and suppressing experimental mesotheliomas compared with the non-targeted alpha-TOS, giving it a potential clinical benefit. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2015
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