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

Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (V.J.F., D.M.T., K.D.T.); Basic Research Program, SAIC-Frederick, Frederick, Maryland (J.E.S., G.S.B., M.L.C.); and Laboratory of Comparative Carcinogenesis (L.K.K.) and Macromolecular Crystallography Laboratory (X.J.), National Cancer Institute at Frederick, Frederick, Maryland

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 isoform of glutathione S-transferase, an enzyme expressed at high levels in many tumors. We have used mouse embryo fibroblasts (MEFs) null for GST (GST^-/-) to show that the absence of GST 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 GST and/or various combinations of -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 GST-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.

Address correspondence to: Kenneth D. Tew, Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111. E-mail: kd_tew{at}fccc.edu

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