JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity

Paul J. Shami, Joseph E. Saavedra, Lai Y. Wang, Challice L. Bonifant, Bhalchandra A. Diwan, Shivendra V. Singh, Yijun Gu, Stephen D. Fox, Gregory S. Buzard, Michael L. Citro, David J. Waterhouse, Keith M. Davies, Xinhua Ji, Larry K. Keefer

Research output: Contribution to journalArticlepeer-review

Abstract

We have previously shown that nitric oxide (NO) inhibits growth and induces differentiation and apoptosis in acute myeloid leukemia cells, with the HL-60 human myeloid leukemia line being particularly sensitive to NO-mediated cytolysis. With the goal of identifying a prodrug that can target NO to the leukemia cells without inducing NO-mediated systemic hypotension, we have screened a series of O2-aryl diazeniumdiolates designed to be stable at physiological pH but to release NO upon reaction with glutathione. O 2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1- ium-1,2-diolate (JS-K) proved to be the most active antiproliferative agent among those tested in HL-60 cells, with an IC50 of 0.2-0.5 μM. After 5 days of exposure to 0.5 μM JS-K, HL-60 cells had differentiated and acquired some of the phenotypic features of normal monocytes. One- to 2-day treatment with JS-K at concentrations of 0.5-1 μM resulted in apoptosis induction in a concentration- and caspase-dependent manner. JS-K also inhibited the growth of solid tumor cell lines but to a lesser extent than HL-60 cells. JS-K was administered i.v. to nonobese diabetic-severe combined immune deficient mice at doses of up to 4 μmol/kg without inducing significant hypotension. The growth of s.c. implanted HL-60 cells was reduced by ∼50% when the mice received i.v. injections three times/week with 4 μmol/kg boluses of JS-K. Histological examination of tumor explants from JS-K-treated animals revealed extensive necrosis. Similar results were seen with s.c. human prostate cancer (PPC-1) xenografts. Our data indicate that JS-K is a promising lead compound for the possible development of a novel class of antineoplastic agents.

Original languageEnglish (US)
Pages (from-to)409-417
Number of pages9
JournalMolecular cancer therapeutics
Volume2
Issue number4
StatePublished - Apr 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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