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Molecular Pharmacology

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Research ArticleArticle

Tumor Cell Responses to a Novel Glutathione S-Transferase–Activated Nitric Oxide-Releasing Prodrug

Victoria J. Findlay, Danyelle M. Townsend, Joseph E. Saavedra, Gregory S. Buzard, Michael L. Citro, Larry K. Keefer, Xinhua Ji and Kenneth D. Tew
Molecular Pharmacology May 2004, 65 (5) 1070-1079; DOI: https://doi.org/10.1124/mol.65.5.1070
Victoria J. Findlay
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Danyelle M. Townsend
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Joseph E. Saavedra
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Gregory S. Buzard
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Michael L. Citro
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Larry K. Keefer
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Xinhua Ji
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Kenneth D. Tew
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Abstract

We have used structure-based design techniques to introduce the drug O2-[2,4-dinitro-5-(N-methyl-N-4-carboxyphenylamino) phenyl] 1-N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO), which is efficiently metabolized to potentially cytolytic nitric oxide by the π isoform of glutathione S-transferase, an enzyme expressed at high levels in many tumors. We have used mouse embryo fibroblasts (MEFs) null for GSTπ (GSTπ-/-) to show that the absence of GSTπ results in a decreased sensitivity to PABA/NO. Cytotoxicity of PABA/NO was also examined in a mouse skin fibroblast (NIH3T3) cell line that was stably transfected with GSTπ and/or various combinations of γ-glutamyl cysteine synthetase and the ATP-binding cassette transporter MRP1. Overexpression of MRP1 conferred the most significant degree of resistance, and in vitro transport studies confirmed that a GSTπ-activated metabolite of PABA/NO was effluxed by MRP1 in a GSH-dependent manner. Additional studies showed that in the absence of MRP1, PABA/NO activated the extracellular-regulated and stress-activated protein kinases ERK, c-Jun NH2-terminal kinase (JNK), and p38. Selective inhibition studies showed that the activation of JNK and p38 were critical to the cytotoxic effects of PABA/NO. Finally, PABA/NO produced antitumor effects in a human ovarian cancer model grown in SCID mice.

  • Received October 2, 2003.
  • Accepted January 22, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 65 (5)
Molecular Pharmacology
Vol. 65, Issue 5
1 May 2004
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Research ArticleArticle

Tumor Cell Responses to a Novel Glutathione S-Transferase–Activated Nitric Oxide-Releasing Prodrug

Victoria J. Findlay, Danyelle M. Townsend, Joseph E. Saavedra, Gregory S. Buzard, Michael L. Citro, Larry K. Keefer, Xinhua Ji and Kenneth D. Tew
Molecular Pharmacology May 1, 2004, 65 (5) 1070-1079; DOI: https://doi.org/10.1124/mol.65.5.1070

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Research ArticleArticle

Tumor Cell Responses to a Novel Glutathione S-Transferase–Activated Nitric Oxide-Releasing Prodrug

Victoria J. Findlay, Danyelle M. Townsend, Joseph E. Saavedra, Gregory S. Buzard, Michael L. Citro, Larry K. Keefer, Xinhua Ji and Kenneth D. Tew
Molecular Pharmacology May 1, 2004, 65 (5) 1070-1079; DOI: https://doi.org/10.1124/mol.65.5.1070
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