Chemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target.
J Biol Chem
; 286(39): 33910-20, 2011 Sep 30.
Article
em En
| MEDLINE
| ID: mdl-21832047
ABSTRACT
The antitumor agent 11ß (CAS 865070-37-7), consisting of a DNA-damaging aniline mustard linked to an androgen receptor (AR) ligand, is known to form covalent DNA adducts and to induce apoptosis potently in AR-positive prostate cancer cells in vitro; it also strongly prevents growth of LNCaP xenografts in mice. The present study describes the unexpectedly strong activity of 11ß against the AR-negative HeLa cells, both in cell culture and tumor xenografts, and uncovers a new mechanism of action that likely explains this activity. Cellular fractionation experiments indicated that mitochondria are the major intracellular sink for 11ß; flow cytometry studies showed that 11ß exposure rapidly induced oxidative stress, mitochondria being an important source of reactive oxygen species (ROS). Additionally, 11ß inhibited oxygen consumption both in intact HeLa cells and in isolated mitochondria. Specifically, 11ß blocked uncoupled oxygen consumption when mitochondria were incubated with complex I substrates, but it had no effect on oxygen consumption driven by substrates acting downstream of complex I in the mitochondrial electron transport chain. Moreover, 11ß enhanced ROS generation in isolated mitochondria, suggesting that complex I inhibition is responsible for ROS production. At the cellular level, the presence of antioxidants (N-acetylcysteine or vitamin E) significantly reduced the toxicity of 11ß, implicating ROS production as an important contributor to cytotoxicity. Collectively, our findings establish complex I inhibition and ROS generation as a new mechanism of action for 11ß, which supplements conventional DNA adduct formation to promote cancer cell death.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Mitocôndrias Hepáticas
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Antineoplásicos Alquilantes
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Complexo I de Transporte de Elétrons
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Mostarda de Anilina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos