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

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.

• Authors: Lan-Feng Dong, Ruth Freeman, Ji Liu, Renata Zobalova, Alvaro Marin-Hernandez, Marina Stantic, Jakub Rohlena, Karel Valis, Sara Rodriguez-Enriquez, Bevan Butcher, Jacob Goodwin, Ulf T Brunk, Paul K Witting, Rafael Moreno-Sanchez, Immo E Scheffler, Stephen J Ralph, Jiri Neuzil
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 5 Pg. 1593-600 (Mar 01 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19223492 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Membrane Proteins
• RNA, Messenger
• Reactive Oxygen Species
• SDHC protein, human
• enhanced green fluorescent protein
• respiratory complex II
• Green Fluorescent Proteins
• Electron Transport Complex II
• alpha-Tocopherol

Topics

• Animals
• Antioxidants (therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Transformation, Neoplastic
• Cells, Cultured
• Colony-Forming Units Assay
• Cricetinae
• Cricetulus
• Electron Transport Complex II (metabolism)
• Fibroblasts (cytology, drug effects, metabolism)
• Green Fluorescent Proteins (genetics)
• Lung (cytology, drug effects, metabolism)
• Lung Neoplasms (metabolism, pathology, prevention & control)
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (metabolism)
• Oxygen Consumption
• RNA, Messenger (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• alpha-Tocopherol (therapeutic use)