Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1.

Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1. Research Abstract Details 

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Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1. Abstract Text:

Ying Huang,Paul E Blower,Ruqing Liu,Zunyan Dai,Anh-Nhan Pham,Hojin Moon,Jialong Fang,Wolfgang ,

PURPOSE: A prerequisite for geldanamycin (GA, NSC122750) to targeting heat shock protein 90 and inhibiting tumor growth is sufficient intracellular drug accumulation. We hypothesized that membrane transporters on tumor cells determine at least in part the response to GA analogues. MATERIALS AND METHODS: To facilitate a systematic study of chemosensitivity across a group of GA analogues with similar chemical structures, we correlated mRNA expression profiles of most known transporters with growth inhibitory potencies of compounds in 60 tumor cell lines (NCI-60). We subsequently validated the gene-drug correlations using cytotoxicity and transport assays. RESULTS: Geldanamycin analogues displayed a range of negative correlations coefficients with ABCB1 (MDR1, or P-glycoprotein) expression. Suppressing ABCB1 in multidrug resistant cells (NCI/ADR-RES and K562/DOX) and ABCB1-transfected cells (BC19) increased sensitivity to GA analogues, as expected for substrates. Moreover, ABCB1-mediated efflux of daunorubicin in K562/DOX cells could be blocked markedly by GA analogues in a dose-dependent fashion. The IC(50) values (half-maximum inhibition of daunorubicin efflux) were 5.5, 7.3 and 12 muM for macbecin II (NSC330500), 17-AAG (NSC330507) and GA, respectively. CONCLUSIONS: These observations demonstrate that GA analogues are substrates as well as inhibitors of ABCB1, suggesting that drug interactions between GA analogues and other agents that are ABCB1 substrates may occur via ABCB1 in normal or tumor cells.

Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1. Publishing Authors By Initials

Y Huang,PE Blower,R Liu,Z Dai,AN Pham,H Moon,J Fang,W ,

For similar proteins: carrier proteins: membrane transport proteins: atp-binding cassette transporters: p-glycoproteins: p-glycoprotein research abstracts see: proteins: carrier proteins: membrane transport proteins: atp-binding cassette transporters: p-glycoproteins: p-glycoprotein research

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Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Pharmaceutical research

VOLUME: 24

Page Numbers: 1702-12

Journal Abbreviation: Pharm. Res.

ISSN: 0724-8741

DAY: 25

MONTH: 04

YEAR: 2007

Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8406521

Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1. Keywords Mesh Terms:

KEYWORDS: P-Glycoprotein

MESH TERMS: physiology

Chemical & Substance for Abstract: Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1. Information

Substance Name: geldanamycin

Registry Number: 30562-34-6

Grant and Affiliation Information for Chemogenomic analysis identifies geldanamycins as substrates and inhibitors of ABCB1.

AFFILIATION: Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA. yhuang@westernu.edu

Country: United States

AGENCY: United States NIGMS

GRANT: GM61390

ACRONYM: GM

MEDLINETA: Pharm Res

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