title: Suppression of tumor growth in vivo by the mitocan alpha-tocopheryl succinate requires respiratory complex II.
abstract: OBJECTIVE
  Vitamin E analogues are potent novel anticancer drugs. The purpose of this study was to elucidate the cellular target by which these agents, represented by alpha-tocopoheryl succinate (alpha-TOS), suppress tumors in vivo, with the focus on the mitochondrial complex II (CII).
  
  
  METHODS
  Chinese hamster lung fibroblasts with functional, dysfunctional, and reconstituted CII were transformed using H-Ras. The cells were then used to form xenografts in immunocompromized mice, and response of the cells and the tumors to alpha-TOS was studied.
  
  
  RESULTS
  The CII-functional and CII-reconstituted cells, unlike their CII-dysfunctional counterparts, responded to alpha-TOS by reactive oxygen species generation and apoptosis execution. Tumors derived from these cell lines reciprocated their responses to alpha-TOS. Thus, growth of CII-functional and CII-reconstituted tumors was strongly suppressed by the agent, and this was accompanied by high level of apoptosis induction in the tumor cells. On the other hand, alpha-TOS did not inhibit the CII-dysfunctional tumors.
  
  
  CONCLUSIONS
  We document in this report a novel paradigm, according to which the mitochondrial CII, which rarely mutates in human neoplasias, is a plausible target for anticancer drugs from the group of vitamin E analogues, providing support for their testing in clinical trials.
authors.affiliation: Apoptosis Research Group and Genomic Research Centre, School of Medical Science, Griffith University, Southport, Queensland, Australia. l.dong@griffith.edu.au
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Dong
authors.forename: Ruth
authors.initials: R
authors.lastname: Freeman
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
authors.forename: Renata
authors.initials: R
authors.lastname: Zobalova
authors.forename: Alvaro
authors.initials: A
authors.lastname: Marin-Hernandez
authors.forename: Marina
authors.initials: M
authors.lastname: Stantic
authors.forename: Jakub
authors.initials: J
authors.lastname: Rohlena
authors.forename: Karel
authors.initials: K
authors.lastname: Valis
authors.forename: Sara
authors.initials: S
authors.lastname: Rodriguez-Enriquez
authors.forename: Bevan
authors.initials: B
authors.lastname: Butcher
authors.forename: Jacob
authors.initials: J
authors.lastname: Goodwin
authors.forename: Ulf T
authors.initials: UT
authors.lastname: Brunk
authors.forename: Paul K
authors.initials: PK
authors.lastname: Witting
authors.forename: Rafael
authors.initials: R
authors.lastname: Moreno-Sanchez
authors.forename: Immo E
authors.initials: IE
authors.lastname: Scheffler
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ralph
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D003412:Cricetulus; D042963:Electron Transport Complex II / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D010101:Oxygen Consumption; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024502:alpha-Tocopherol / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D008565:Membrane Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C108096:SDHC protein, human; C485184:enhanced green fluorescent protein; C478189:respiratory complex II; D049452:Green Fluorescent Proteins; D042963:Electron Transport Complex II; D024502:alpha-Tocopherol