Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II.
Mitochondrial complex II (CII) has been recently identified as a novel target for anti-cancer drugs. Mitochondrially targeted vitamin E succinate (MitoVES) is modified so that it is preferentially localized to mitochondria, greatly enhancing its pro-apoptotic and anti-cancer activity. Using genetically manipulated cells, MitoVES caused apoptosis and generation of reactive oxygen species (ROS) in CII-proficient malignant cells but not their CII-dysfunctional counterparts. MitoVES inhibited the succinate dehydrogenase (SDH) activity of CII with IC(50) of 80 μM, whereas the electron transfer from CII to CIII was inhibited with IC(50) of 1.5 μM. The agent had no effect either on the enzymatic activity of CI or on electron transfer from CI to CIII. Over 24 h, MitoVES caused stabilization of the oxygen-dependent destruction domain of HIF1α fused to GFP, indicating promotion of the state of pseudohypoxia. Molecular modeling predicted the succinyl group anchored into the proximal CII ubiquinone (UbQ)-binding site and successively reduced interaction energies for serially shorter phytyl chain homologs of MitoVES correlated with their lower effects on apoptosis induction, ROS generation, and SDH activity. Mutation of the UbQ-binding Ser(68) within the proximal site of the CII SDHC subunit (S68A or S68L) suppressed both ROS generation and apoptosis induction by MitoVES. In vivo studies indicated that MitoVES also acts by causing pseudohypoxia in the context of tumor suppression. We propose that mitochondrial targeting of VES with an 11-carbon chain localizes the agent into an ideal position across the interface of the mitochondrial inner membrane and matrix, optimizing its biological effects as an anti-cancer drug.
School of Medical Science, Griffith University, Southport 4222, Queensland, Australia.
Lan-Feng
LF
Dong
Victoria J A
VJ
Jameson
David
D
Tilly
Jiri
J
Cerny
Elahe
E
Mahdavian
Alvaro
A
Marín-Hernández
Luz
L
Hernández-Esquivel
Sara
S
Rodríguez-Enríquez
Jan
J
Stursa
Paul K
PK
Witting
Bela
B
Stantic
Jakub
J
Rohlena
Jaroslav
J
Truksa
Katarina
K
Kluckova
Jeffrey C
JC
Dyason
Miroslav
M
Ledvina
Brian A
BA
Salvatore
Rafael
R
Moreno-Sánchez
Mark J
MJ
Coster
Stephen J
SJ
Ralph
Robin A J
RA
Smith
Jiri
J
Neuzil
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D016503:Drug Delivery Systems / Q000379:methods*; D004579:Electron Transport; D042963:Electron Transport Complex II / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013385:Succinate Dehydrogenase; D014810:Vitamin E / Q000008:administration & dosage* / Q000494:pharmacology
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D014810:Vitamin E; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase