Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity.

Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity. Research Abstract Details 

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Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity. Abstract Text:

Son B Le,M Katie Hailer,Sarah Buhrow,Qi Wang,Karen Flatten,Peter Pediaditakis,Keith C Bible,Lionel D Lewis,Edward A Sausville,Yuan-Ping Pang,Matthew M Ames,John J Lemasters,Ekhson L Holmuhamedov,Scott H Kaufmann,

Adaphostin is a dihydroquinone derivative that is undergoing extensive preclinical testing as a potential anticancer drug. Previous studies have suggested that the generation of reactive oxygen species (ROS) plays a critical role in the cytotoxicity of this agent. In this study, we investigated the source of these ROS. Consistent with the known chemical properties of dihydroquinones, adaphostin simultaneously underwent oxidation to the corresponding quinone and generated ROS under aqueous conditions. Interestingly, however, this quinone was not detected in intact cells. Instead, high performance liquid chromatography demonstrated that adaphostin was concentrated by up to 300-fold in cells relative to the extracellular medium and that the highest concentration of adaphostin (3000-fold over extracellular concentrations) was detected in mitochondria. Consistent with a mitochondrial site for adaphostin action, adaphostin-induced ROS production was diminished by >75% in MOLT-4 rho(0) cells, which lack mitochondrial electron transport, relative to parental MOLT-4 cells. In addition, inhibition of oxygen consumption was observed when intact cells were treated with adaphostin. Loading of isolated mitochondria to equivalent adaphostin concentrations caused inhibition of uncoupled oxygen consumption in mitochondria incubated with the complex I substrates pyruvate and malate or the complex II substrate succinate. Further analysis demonstrated that adaphostin had no effect on pyruvate or succinate dehydrogenase activity. Instead, adaphostin inhibited reduced decylubiquinone-induced cytochrome c reduction, identifying complex III as the site of inhibition by this agent. Moreover, adaphostin enhanced the production of ROS by succinate-charged mitochondria. Collectively, these observations demonstrate that mitochondrial respiration rather than direct redox cycling of the hydroquinone moiety is a source of adaphostin-induced ROS and identify complex III as a potential target for antineoplastic agents.

Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity. Publishing Authors By Initials

SB Le,MK Hailer,S Buhrow,Q Wang,K Flatten,P Pediaditakis,KC Bible,LD Lewis,EA Sausville,YP Pang,MM Ames,JJ Lemasters,EL Holmuhamedov,SH Kaufmann,

For similar inorganic chemicals: electrolytes: ions: anions: oxides: peroxides: superoxides research abstracts see: inorganic chemicals: electrolytes: ions: anions: oxides: peroxides: superoxides research

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Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 8860-72

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 9

MONTH: 01

YEAR: 2007

Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity. Keywords Mesh Terms:

KEYWORDS: Superoxides

MESH TERMS: metabolism

Chemical & Substance for Abstract: Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity. Information

Substance Name: DNA-Formamidopyrimidine Glycosylase

Registry Number: EC 3.2.2.23

Grant and Affiliation Information for Inhibition of mitochondrial respiration as a source of adaphostin-induced reactive oxygen species and cytotoxicity.

AFFILIATION: Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

Country: United States

AGENCY: United States NCI

GRANT: R01 CA85972

ACRONYM: CA

MEDLINETA: J Biol Chem

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