Suppression of Tumor Growth In vivo by the Mitocan α-tocopheryl Succinate Requires Respiratory Complex II
- Lan-Feng Dong1,
- Ruth Freeman1,
- Ji Liu1,
- Renata Zobalova1,3,
- Alvaro Marin-Hernandez4,
- Marina Stantic1,
- Jakub Rohlena3,
- Karel Valis3,
- Sara Rodriguez-Enriquez4,
- Bevan Butcher2,
- Jacob Goodwin2,
- Ulf T. Brunk5,
- Paul K. Witting6,
- Rafael Moreno-Sanchez4,
- Immo E. Scheffler7,
- Stephen J. Ralph2 and
- Jiri Neuzil1,3
- Authors' Affiliations:1Apoptosis Research Group and 2Genomic Research Centre, School of Medical Science, Griffith University, Southport, Queensland, Australia; 3Molecular Therapy Group, Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague, Czech Republic; 4Department of Biochemistry, National Institute of Cardiology, Mexico City, Mexico; 5Division of Pharmacology, University of Linkoping, Linkoping, Sweden; 6ANZAC Research Institute, Concord Hospital, Concord, Sydney, New South Wales, Australia; and 7Division of Biology, University of California, San Diego, California
- Requests for reprints:
Jiri Neuzil, Apoptosis Research Group, School of Medical Science, Griffith University, Gold Coast Campus, Southport, 4222, Queensland, Australia. Phone: 61-2-555-29109; Fax: 61-2-555-28444; E-mail: j.neuzil{at}griffith.edu.au or Lan-Feng Dong, Apoptosis Research Group, School of Medical Science, Griffith University, Gold Coast Campus, Southport, 4222, Queensland, Australia. Phone: 61-2-555-29109; Fax: 61-2-555-28703; E-mail: l.dong{at}griffith.edu.au.
Abstract
Purpose: 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 α-tocopoheryl succinate (α-TOS), suppress tumors in vivo, with the focus on the mitochondrial complex II (CII).
Experimental Design: 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 α-TOS was studied.
Results: The CII-functional and CII-reconstituted cells, unlike their CII-dysfunctional counterparts, responded to α-TOS by reactive oxygen species generation and apoptosis execution. Tumors derived from these cell lines reciprocated their responses to α-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, α-TOS did not inhibit the CII-dysfuntional 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.
Footnotes
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Grant support: Australian Research Council (J. Neuzil and P.K. Witting), the Queensland Cancer Fund, the Grant Agency of the Czech Republic and the Grant Agency of the Academy of Sciences of the Czech Republic awarded to J. Neuzil. The paper forms a part of the PhD thesis of R. Freenan.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted November 6, 2008.
- Received September 23, 2008.
- Revision received November 4, 2008.
