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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Identification of Chemosensitivity Nodes for Vinblastine through Small Interfering RNA High-Throughput Screens

Carolyn A. Kitchens, Peter R. McDonald, Tong Ying Shun, Ian F. Pollack and John S. Lazo
Journal of Pharmacology and Experimental Therapeutics December 2011, 339 (3) 851-858; DOI: https://doi.org/10.1124/jpet.111.184879
Carolyn A. Kitchens
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Peter R. McDonald
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Tong Ying Shun
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Ian F. Pollack
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John S. Lazo
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Abstract

Discovering chemosensitivity pathways or nodes is an attractive strategy for formulating new drug combinations for cancer. Microtubules are among the most successful anticancer drug targets. Therefore, we implemented a small interfering RNA (siRNA) synthetic lethal screen targeting 5520 unique druggable genes to identify novel chemosensitivity nodes for vinblastine, a microtubule-destabilizing agent used clinically. We transiently transfected human glioblastoma cells with siRNAs for 48 h and then treated cells with a sublethal concentration of vinblastine. Forty-eight hours later, we analyzed cell viability and, using a series of statistical methods, identified 65 gene products that, when suppressed, sensitized glioblastoma cells to vinblastine. After completion of the secondary assays, we focused on one siRNA, B-cell lymphoma extra large (BCL-xL), because of its role in the intrinsic apoptosis signaling pathway as well as the availability of pharmacological inhibitors. We found that nontoxic concentrations of 4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide (ABT-263), an inhibitor of the BCL-2 family members (BCL-2, BCL-xL, and BCL-w), sensitized glioblastoma and non–small-cell lung cancer cells to vinblastine and induced apoptosis through the intrinsic cell death pathway. These results illustrate the usefulness of unbiased siRNA screens as a method for identifying potential novel anticancer therapeutic combinations.

Footnotes

  • This work was supported by the National Institutes of Health National Cancer Institute [Grant CA078039]; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS40923]; the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant AI063021]; and a grant from the Fiske Drug Discovery Fund.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.184879.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    GBM
    glioblastoma multiforme
    ABT-263
    4-[4-[[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-morpholin-4-yl-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylbenzamide
    BCL-2
    B-cell lymphoma 2
    BCL-xL
    B-cell lymphoma extra large
    DMSO
    dimethyl sulfoxide
    FDR
    false discovery rate
    MAD
    median absolute deviation
    HTS
    high-throughput screening
    PBS
    phosphate-buffered saline
    RFU
    relative fluorescent unit
    siRNA
    small interfering RNA
    SCR
    scrambled
    VBL
    vinblastine.

  • Received June 9, 2011.
  • Accepted August 30, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 339 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 339, Issue 3
1 Dec 2011
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Vinblastine Sensitization by BCL-xL siRNA and ABT-263

Carolyn A. Kitchens, Peter R. McDonald, Tong Ying Shun, Ian F. Pollack and John S. Lazo
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 851-858; DOI: https://doi.org/10.1124/jpet.111.184879

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Vinblastine Sensitization by BCL-xL siRNA and ABT-263

Carolyn A. Kitchens, Peter R. McDonald, Tong Ying Shun, Ian F. Pollack and John S. Lazo
Journal of Pharmacology and Experimental Therapeutics December 1, 2011, 339 (3) 851-858; DOI: https://doi.org/10.1124/jpet.111.184879
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