Proteomic analysis identifies oxidative stress induction by adaphostin.

Proteomic analysis identifies oxidative stress induction by adaphostin. Research Abstract Details 

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Proteomic analysis identifies oxidative stress induction by adaphostin. Abstract Text:

Luke H Stockwin,Maja A Bumke,Sherry X Yu,Simon P Webb,Jack R Collins,Melinda G Hollingshead,Dianne L Newton,

PURPOSE: Activities distinct from inhibition of Bcr/abl have led to adaphostin (NSC 680410) being described as "a drug in search of a mechanism." In this study, proteomic analysis of adaphostin-treated myeloid leukemia cell lines was used to further elucidate a mechanism of action. EXPERIMENTAL DESIGN: HL60 and K562 cells treated with adaphostin for 6, 12, or 24 h were analyzed using two-dimensional PAGE. Differentially expressed spots were excised, digested with trypsin, and analyzed by liquid chromatography-tandem mass spectrometry. The contribution of the redox-active hydroquinone group in adaphostin was also examined by carrying out proteomic analysis of HL60 cells treated with a simple hydroquinone (1,4-dihydroxybenzene) or H(2)O(2). RESULTS: Analysis of adaphostin-treated cells identified 49 differentially expressed proteins, the majority being implicated in the response to oxidative stress (e.g., CALM, ERP29, GSTP1, PDIA1) or induction of apoptosis (e.g., LAMA, FLNA, TPR, GDIS). Interestingly, modulation of these proteins was almost fully prevented by inclusion of an antioxidant, N-acetylcysteine. Validation of the proteomic data confirmed GSTP1 as an adaphostin resistance gene. Subsequent analysis of HL60 cells treated with 1,4-dihydroxybenzene or H(2)O(2) showed similar increases in intracellular peroxides and an almost identical proteomic profiles to that of adaphostin treatment. Western blotting of a panel of cell lines identified Cu/Zn superoxide dismutase (SOD) as correlating with adaphostin resistance. The role of SOD as a second adaphostin resistance gene was confirmed by demonstrating that inhibition of SOD using diethyldithiocarbamate increased adaphostin sensitivity, whereas transfection of SOD I attenuated toxicity. Importantly, treatment with 1,4-dihydroxybenzene or H(2)O(2) replicated adaphostin-induced Bcr/abl polypeptide degradation, suggesting that kinase inhibition is a ROS-dependent phenomenon. CONCLUSION: Adaphostin should be classified as a redox-active-substituted dihydroquinone.

Proteomic analysis identifies oxidative stress induction by adaphostin. Publishing Authors By Initials

LH Stockwin,MA Bumke,SX Yu,SP Webb,JR Collins,MG Hollingshead,DL Newton,

For similar biological sciences: biochemistry: proteomics research abstracts see: biological sciences: biochemistry: proteomics research

PUBMED ID PMID:

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Proteomic analysis identifies oxidative stress induction by adaphostin. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Clinical cancer research : an official journal of

VOLUME: 13

Page Numbers: 3667-81

Journal Abbreviation: Clin. Cancer Res.

ISSN: 1078-0432

DAY: 15

MONTH: Jun

YEAR: 2007

Proteomic analysis identifies oxidative stress induction by adaphostin. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 9502500

Proteomic analysis identifies oxidative stress induction by adaphostin. Keywords Mesh Terms:

KEYWORDS: Proteomics

MESH TERMS: drug effects

Chemical & Substance for Abstract: Proteomic analysis identifies oxidative stress induction by adaphostin. Information

Substance Name: Adamantane

Registry Number: 281-23-2

Grant and Affiliation Information for Proteomic analysis identifies oxidative stress induction by adaphostin.

AFFILIATION: Developmental Therapeutics Program, Science Applications International Corporation Frederick, Frederick, Maryland 21702, USA.

Country: United States

AGENCY: United States NCI

GRANT: N01-CO-12400

ACRONYM: CO

MEDLINETA: Clin Cancer Res

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