JS-K, a Glutathione/Glutathione S-Transferase-activated Nitric Oxide Donor of the Diazeniumdiolate Class with Potent Antineoplastic Activity1

• Published in: Molecular cancer therapeutics Vol. 2; no. 4; p. 409
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: American Association for Cancer Research 01-04-2003
• ISSN: 1535-7163; 1538-8514

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 O 2 -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 IC 50 of 0.2–0.5 μ m . After 5 days of exposure to 0.5 μ m 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 μ m 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.