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Disruption of the mitochondrial thioredoxin system as a cell death mechanism of cationic triphenylmethanes.
- Source :
-
Free radical biology & medicine [Free Radic Biol Med] 2011 Apr 01; Vol. 50 (7), pp. 811-20. Date of Electronic Publication: 2011 Jan 04. - Publication Year :
- 2011
-
Abstract
- Alterations in mitochondrial structure and function are a hallmark of cancer cells compared to normal cells and thus targeting mitochondria has emerged as an novel approach to cancer therapy. The mitochondrial thioredoxin 2 (Trx2) system is critical for cell viability, but its role in cancer biology is not well understood. Recently some cationic triphenylmethanes such as brilliant green (BG) and gentian violet were shown to have antitumor and antiangiogenic activity with unknown mechanisms. Here we demonstrate that BG killed cells at nanomolar concentrations and targeted mitochondrial Trx2, which was oxidized and degraded. HeLa cells were more sensitive to BG than fibroblasts. In HeLa cells, Trx2 down-regulation by siRNA resulted in increased sensitivity to BG, whereas for fibroblasts, the same treatments had no effect. BG was observed to accumulate in mitochondria and cause a rapid and dramatic decrease in mitochondrial Trx2 protein. With a redox Western blot method, we found that treatment with BG caused oxidation of both Trx1 and Trx2, followed by release of cytochrome c and apoptosis-inducing factor from the mitochondria into the cytosol. Moreover, this treatment resulted in an elevation of the mRNA level of Lon protease, a protein quality control enzyme in the mitochondrial matrix, suggesting that the oxidized Trx2 may be degraded by Lon protease.<br /> (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Subjects :
- Angiogenesis Inhibitors chemistry
Angiogenesis Inhibitors pharmacology
Angiogenesis Inhibitors therapeutic use
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Apoptosis Inducing Factor analysis
Apoptosis Inducing Factor metabolism
Cations chemistry
Cell Survival drug effects
Cytochromes c analysis
Cytochromes c metabolism
Fibroblasts
Gentian Violet chemistry
Gentian Violet therapeutic use
HeLa Cells
Humans
Neoplasms drug therapy
Oxidation-Reduction
Protease La metabolism
Quaternary Ammonium Compounds chemistry
Quaternary Ammonium Compounds therapeutic use
RNA, Small Interfering pharmacology
Reactive Oxygen Species metabolism
Thioredoxins biosynthesis
Trityl Compounds chemistry
Trityl Compounds pharmacology
Trityl Compounds therapeutic use
Up-Regulation
Apoptosis drug effects
Gentian Violet pharmacology
Mitochondria metabolism
Quaternary Ammonium Compounds pharmacology
Thioredoxins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4596
- Volume :
- 50
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 21215310
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2010.12.036