JS-K, a glutathione/glutathione S-transferase-activated nitric oxide donor of the diazeniumdiolate class with potent antineoplastic activity.
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.
Shami
Paul J
PJ
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
Saavedra
Joseph E
JE
Wang
Lai Y
LY
Bonifant
Challice L
CL
Diwan
Bhalchandra A
BA
Singh
Shivendra V
SV
Gu
Yijun
Y
Fox
Stephen D
SD
Buzard
Gregory S
GS
Citro
Michael L
ML
Waterhouse
David J
DJ
Davies
Keith M
KM
Ji
Xinhua
X
Keefer
Larry K
LK
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
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