title: Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: a new paradigm for effective cancer therapy.
abstract: Mitochondria are emerging as intriguing targets for anti-cancer agents. We tested here a novel approach, whereby the mitochondrially targeted delivery of anti-cancer drugs is enhanced by the addition of a triphenylphosphonium group (TPP(+)). A mitochondrially targeted analog of vitamin E succinate (MitoVES), modified by tagging the parental compound with TPP(+), induced considerably more robust apoptosis in cancer cells with a 1-2 log gain in anti-cancer activity compared to the unmodified counterpart, while maintaining selectivity for malignant cells. This is because MitoVES associates with mitochondria and causes fast generation of reactive oxygen species that then trigger mitochondria-dependent apoptosis, involving transcriptional modulation of the Bcl-2 family proteins. MitoVES proved superior in suppression of experimental tumors compared to the untargeted analog. We propose that mitochondrially targeted delivery of anti-cancer agents offers a new paradigm for increasing the efficacy of compounds with anti-cancer activity.
authors.affiliation: School of Medical Science, Griffith University, Southport, QLD 4222, Australia. l.dong@griffith.edu.au
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Dong
authors.forename: Victoria J A
authors.initials: VJ
authors.lastname: Jameson
authors.forename: David
authors.initials: D
authors.lastname: Tilly
authors.forename: Lubomir
authors.initials: L
authors.lastname: Prochazka
authors.forename: Jakub
authors.initials: J
authors.lastname: Rohlena
authors.forename: Karel
authors.initials: K
authors.lastname: Valis
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Truksa
authors.forename: Renata
authors.initials: R
authors.lastname: Zobalova
authors.forename: Elahe
authors.initials: E
authors.lastname: Mahdavian
authors.forename: Katarina
authors.initials: K
authors.lastname: Kluckova
authors.forename: Marina
authors.initials: M
authors.lastname: Stantic
authors.forename: Jan
authors.initials: J
authors.lastname: Stursa
authors.forename: Ruth
authors.initials: R
authors.lastname: Freeman
authors.forename: Paul K
authors.initials: PK
authors.lastname: Witting
authors.forename: Erik
authors.initials: E
authors.lastname: Norberg
authors.forename: Jacob
authors.initials: J
authors.lastname: Goodwin
authors.forename: Brian A
authors.initials: BA
authors.lastname: Salvatore
authors.forename: Jana
authors.initials: J
authors.lastname: Novotna
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Turanek
authors.forename: Miroslav
authors.initials: M
authors.lastname: Ledvina
authors.forename: Pavel
authors.initials: P
authors.lastname: Hozak
authors.forename: Boris
authors.initials: B
authors.lastname: Zhivotovsky
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Coster
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ralph
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016503:Drug Delivery Systems; D004358:Drug Therapy / Q000639:trends; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism*; D023421:Models, Animal; D058990:Molecular Targeted Therapy; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D024505:Tocopherols / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D009943:Organophosphorus Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D024505:Tocopherols