Mitochondrial targeting of α-tocopheryl succinate enhances its anti-mesothelioma efficacy

Our plain-English summary of Mitochondrial targeting of α-tocopheryl succinate enhances its anti-mesothelioma efficacy, by J. Kovarova, M. Bajzikova, M. Vondrusova, et al (Redox Report, 2014).

The study

• Authors: J. Kovarova, M. Bajzikova, M. Vondrusova, J. Stursa, J. Goodwin, M. Nguyen, R. Zobalova, E.A. Pesdar, J. Truksa, M. Tomasetti, L.F. Dong, J. Neuzil
• Journal: Redox Report
• Published: 2014;19(1):16-25
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Unlabelled: 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 α-tocopheryl succinate (α-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 α-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 α-TOS, giving it a potential clinical benefit.

In plain English

This was a laboratory study. The experiments did not involve asbestos exposure or test MitoVES in people. The authors tested MitoVES, a vitamin E compound modified to collect inside mitochondria, the energy-producing parts of cells. They compared it with the original compound, α-tocopheryl succinate (α-TOS), in five malignant mesothelioma cell lines and in tumours grown under the skin of nude mice. In the cell lines, MitoVES killed half the cells at doses up to about one hundred times lower. A labelled form of MitoVES gathered only in mitochondria, unless their membrane potential was first disrupted. It also produced high levels of reactive oxygen species, a damaging form of oxygen. Cells with a weakened mitochondrial component called complex II showed little cell death after MitoVES. In mice, MitoVES at 1 μmol per dose twice weekly suppressed tumour growth by more than 90 percent, versus about 80 percent for α-TOS at 15 μmol; no obvious toxicity was seen. The authors also briefly described treating one mesothelioma patient with topical α-TOS, outside these experiments. The authors concluded that the results were encouraging and of potential clinical benefit.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of mesothelioma cell lines plus an animal experiment with tumours grown in mice (xenografts)
• Who was studied: Human malignant mesothelioma cell lines Ist-Mes-2, MM-BI, Meso-2 and H28, and the murine (mouse) AE17 mesothelioma cell line. Also athymic Balb-c nu/nu mice injected under the skin with Ist-Mes-2 cells (the mouse tumour data are given as n = 3). The work was done in the Czech Republic and Australia. Dates are not given.
• Exposure: No asbestos exposure was studied. The tested agents were α-tocopheryl succinate (α-TOS) and its mitochondria-targeted form MitoVES, applied to cells in culture. In mice, they were injected into the peritoneum twice per week at 15 μmol α-TOS or 1 μmol MitoVES.
• Main results:
  • In all five cell lines, the IC50 (the concentration needed to kill half the cells) was lower for MitoVES than for α-TOS. Values for α-TOS versus MitoVES: H28 26.6 vs 2.0; Ist-Mes-2 37.7 vs 0.25; Meso-2 32.9 vs 0.9; MM-BI 25.6 vs 0.75; AE17 37.5 vs 0.5. The table does not print units.
  • In the cell lines, MitoVES killed almost all cells within 24 hours at more than 2.5 μM. Similar killing required 50 to 100 μM α-TOS.
  • In mesothelioma cells, α-TOS produced very low levels of reactive oxygen species, while MitoVES caused rapid loss of mitochondrial membrane potential.
  • A fluorescently labelled form of MitoVES was located only in the mitochondria of the mesothelioma cells.
  • When the mitochondrial membrane potential of Ist-Mes-2 cells was first disrupted with 2 μM CCCP, MitoVES no longer localized only to mitochondria, and the cell death it caused was suppressed.
  • At 5 μM and within 1 hour, MitoVES destabilized larger assemblies of respiratory complexes (supercomplexes) in Ist-Mes-2 and H28 cells.
  • Ist-Mes-2 cells with reduced mitochondrial complex II (SDHC knock-down) showed low levels of cell death after MitoVES. The authors took this as pointing to complex II as the drug's target.
  • In nude mice with Ist-Mes-2 tumours, MitoVES at 1 μmol per dose twice weekly suppressed tumour progression by more than 90%. α-TOS at 15 μmol gave about 80% tumour growth inhibition. The two agents were given at different doses.
  • The authors did not observe obvious toxicity of MitoVES in the mice.
  • Outside the experiments, the authors mentioned treating a single mesothelioma patient with topical α-TOS (not MitoVES). The patient survived 4 years after diagnosis, against a predicted ~6 months, but the tumour later grew and the patient died of the disease.
• The authors' conclusion: The authors concluded that their results on MitoVES were highly encouraging and of potential clinical benefit for malignant mesothelioma.
• Limitations the authors state:
  • The authors stated that the exact mechanism by which MitoVES affects the mitochondrial supercomplexes is yet to be established.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Apoptosis, Reactive Oxygen Species (ROS).

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