title: JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity.
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 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 microM. After 5 days of exposure to 0.5 micro 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 microM 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 micromol/kg without inducing significant hypotension. The growth of s.c. implanted HL-60 cells was reduced by approximately 50% when the mice received i.v. injections three times/week with 4 micromol/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.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, University of Utah and Salt Lake City Veterans' Administration Medical Centers, Salt Lake City, Utah 84148, USA. p.shami@m.cc.utsh.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shami
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.forename: Lai Y
authors.initials: LY
authors.lastname: Wang
authors.forename: Challice L
authors.initials: CL
authors.lastname: Bonifant
authors.forename: Bhalchandra A
authors.initials: BA
authors.lastname: Diwan
authors.forename: Shivendra V
authors.initials: SV
authors.lastname: Singh
authors.forename: Yijun
authors.initials: Y
authors.lastname: Gu
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Fox
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Buzard
authors.forename: Michael L
authors.initials: ML
authors.lastname: Citro
authors.forename: David J
authors.initials: DJ
authors.lastname: Waterhouse
authors.forename: Keith M
authors.initials: KM
authors.lastname: Davies
authors.forename: Xinhua
authors.initials: X
authors.lastname: Ji
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001391:Azo Compounds / Q000494:pharmacology*; D002454:Cell Differentiation; D002455:Cell Division; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007938:Leukemia / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008956:Models, Chemical; D008958:Models, Molecular; D009000:Monocytes / Q000378:metabolism; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D013997:Time Factors; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D020030:Nitric Oxide Donors; C474958:O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate; D010879:Piperazines; D011355:Prodrugs; C452539:diazeniumdiolate; D009569:Nitric Oxide; D005982:Glutathione Transferase; D005978:Glutathione