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Suppression of tumor growth in vivo by the mitocan alpha-tocopheryl succinate requires respiratory complex II.

  • Author(s): Dong, Lan-Feng
  • Freeman, Ruth
  • Liu, Ji
  • Zobalova, Renata
  • Marin-Hernandez, Alvaro
  • Stantic, Marina
  • Rohlena, Jakub
  • Valis, Karel
  • Rodriguez-Enriquez, Sara
  • Butcher, Bevan
  • Goodwin, Jacob
  • Brunk, Ulf T
  • Witting, Paul K
  • Moreno-Sanchez, Rafael
  • Scheffler, Immo E
  • Ralph, Stephen J
  • Neuzil, Jiri
  • et al.

Published Web Location

https://clincancerres.aacrjournals.org/content/15/5/1593.long
No data is associated with this publication.
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 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-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.

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