Suppression of Tumor Growth In vivo by the Mitocan alpha-tocopheryl Succinate Requires Respiratory Complex II

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 alpha-tocopoheryl succinate (alpha-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 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-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.

Freeman, RuthGriffith University (author)
Liu, JiGriffith University (author)
Zobalova, RenataGriffith University (author)
Marin-Hernandez, AlvaroNational Institute of Cardiology, Mexico City (author)
Stantic, MarinaGriffith University (author)
Rohlena, JakubAcadamy of Science, Czech Republic (author)
Valis, KarelAcadamy of Science, Czech Republic (author)
Rodriguez-Enriquez, SaraNational Institute of Cardiology, Mexico City (author)
Butcher, BevanGriffith University (author)
Goodwin, JacobGriffith University (author)
Brunk, UlfLinköpings universitet,Farmakologi,Hälsouniversitetet(Swepub:liu)ulfbr20 (author)
Witting, Paul KANZAC Research Institute (author)
Moreno-Sanchez, RafaelNational Institute of Cardiology, Mexico City (author)
Scheffler, Immo EUniversity California at San Diego (author)
Ralph, Stephen JGriffith University (author)
Neuzil, JiriGriffith University (author)
Griffith UniversityNational Institute of Cardiology, Mexico City (creator_code:org_t)

By the author/editor: Dong, Lan-Feng; Freeman, Ruth; Liu, Ji; Zobalova, Renata; Marin-Hernandez, ...; Stantic, Marina; show more...; Rohlena, Jakub; Valis, Karel; Rodriguez-Enriqu ...; Butcher, Bevan; Goodwin, Jacob; Brunk, Ulf; Witting, Paul K; Moreno-Sanchez, ...; Scheffler, Immo ...; Ralph, Stephen J; Neuzil, Jiri; show less...

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