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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 August 31, 2011, jpet.111.184879; 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 drugs targets. Therefore, we implemented a small interfering RNA (siRNA) synthetic lethal screen targeting 5,520 unique druggable genes to identify novel chemosensitivity nodes for vinblastine, a clinically used microtubule destabilizing agent. We transiently transfected human glioblastoma cells with siRNAs for 48 h and then treated cells with a sub-lethal concentration of vinblastine. Forty-eight h 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, BCL-xL, because of its role in the intrinsic apoptosis signaling pathway, as well as the availability of pharmacological inhibitors. We found nontoxic concentrations of 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.

  • anticancer agents
  • glioblastoma cells
  • high throughput screening
  • microtubules
  • RNA/siRNA
  • Received June 9, 2011.
  • Revision received August 29, 2011.
  • Accepted August 30, 2011.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 365 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 365, Issue 2
1 May 2018
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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 August 31, 2011, jpet.111.184879; DOI: https://doi.org/10.1124/jpet.111.184879

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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 August 31, 2011, jpet.111.184879; DOI: https://doi.org/10.1124/jpet.111.184879
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