Suppression of tumor growth in vivo by the mitocan alpha-tocopheryl succinate requires respiratory complex II.
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.
Dong
Lan-Feng
LF
Apoptosis Research Group and Genomic Research Centre, School of Medical Science, Griffith University, Southport, Queensland, Australia. l.dong@griffith.edu.au
Freeman
Ruth
R
Liu
Ji
J
Zobalova
Renata
R
Marin-Hernandez
Alvaro
A
Stantic
Marina
M
Rohlena
Jakub
J
Valis
Karel
K
Rodriguez-Enriquez
Sara
S
Butcher
Bevan
B
Goodwin
Jacob
J
Brunk
Ulf T
UT
Witting
Paul K
PK
Moreno-Sanchez
Rafael
R
Scheffler
Immo E
IE
Ralph
Stephen J
SJ
Neuzil
Jiri
J
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*
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