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


CONCLUSIONS
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.
Jaromira
J
Kovarova
Martina
M
Bajzikova
Magdalena
M
Vondrusova
Jan
J
Stursa
Jacob
J
Goodwin
Maria
M
Nguyen
Renata
R
Zobalova
Elham Alizadeh
EA
Pesdar
Jaroslav
J
Truksa
Marco
M
Tomasetti
Lan-Feng
LF
Dong
Jiri
J
Neuzil
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; C000590646:MitoVE11S; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D042963:Electron Transport Complex II; D024502:alpha-Tocopherol
Apoptosis; Mesothelioma; Mitochondrial targeting; Reactive oxygen species; Respiratory complexes; Vitamin E analogues