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Chemogenomic Analysis Identifies Geldanamycins as Substrates and Inhibitors of ABCB1

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Abstract

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 IC50 values (half-maximum inhibition of daunorubicin efflux) were 5.5, 7.3 and 12 μM 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.

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Abbreviations

NCI:

The National Cancer Institute

DTP:

Developmental Therapeutics Program

SiRNA:

small interfering RNA

ABC:

ATP-binding cassette

SRB:

sulforhodamine B

GA:

geldanamycin

Hsp90:

heat shock protein 90

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Acknowledgments

We thank the staff of NCI DTP for generation of the pharmacological database used in this study. This work was supported by NIH grant GM61390 and by the Food and Drug Administration.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA, 91766, USA

    Ying Huang & Anh-Nhan Pham

  2. Leadscope Inc., Columbus, OH, 43212, USA

    Paul E. Blower

  3. Program of Pharmacogenomics, Department of Pharmacology, Comprehensive Cancer Center, College of Medicine and Public Health, The Ohio State University, Columbus, OH, 43210, USA

    Paul E. Blower, Zunyan Dai & Wolfgang Sadée

  4. School of Public Health, Sun Yat-sen University, Guangzhou, China

    Ruqing Liu

  5. Division of Biometry and Risk Assessment, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, 72079, USA

    Hojin Moon

  6. Division of Biochemical Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR, 72079, USA

    Jialong Fang

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  1. Ying Huang
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Correspondence to Ying Huang.

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11095_2007_9300_MOESM1_ESM.ppt

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Huang, Y., Blower, P.E., Liu, R. et al. Chemogenomic Analysis Identifies Geldanamycins as Substrates and Inhibitors of ABCB1. Pharm Res 24, 1702–1712 (2007). https://doi.org/10.1007/s11095-007-9300-x

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  • DOI: https://doi.org/10.1007/s11095-007-9300-x

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