title: JS-K, an arylating nitric oxide (NO) donor, has synergistic anti-leukemic activity with cytarabine (ARA-C).
abstract: We have designed prodrugs that release nitric oxide (NO) on metabolism by glutathione S-transferases (GST). This design exploits the upregulation of GST in acute myeloid leukemia (AML) cells. O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent anti-leukemic activity. HL-60 myeloid leukemia cells were used for in vitro studies of the combination of JS-K with daunorubicin (DAUNO), cytarabine (ARA-C) or etoposide (ETOP) using the median effect method to determine synergistic, antagonistic, or additive effects. Combinations of JS-K added simultaneously, 2h before or 2h after the other compounds were used. JS-K and DAUNO were antagonistic in all three drug sequences. JS-K and ETOP were also antagonistic but to a lesser degree. JS-K and ARA-C showed strong synergy. The combination index at the 50% fraction affected was 0.37+/-0.23, 0.24+/-0.27, and 0.15+/-0.11 for simultaneous, JS-K first and ARA-C first additions, respectively. JS-K by itself induced DNA strand breaks at relatively high concentrations. However, at submicromolar concentrations, it significantly augmented ARA-C-induced DNA strand breaks. NMR spectroscopy revealed no evidence of chemical interaction between JS-K and the other chemotherapeutic agents. We conclude that ARA-C and JS-K have synergistic anti-leukemic activity and warrant further exploration in combination.
authors.affiliation: Medical Oncology, University of Utah, Salt Lake City, UT, United States. paul.shami@utah.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Shami
authors.forename: Anna E
authors.initials: AE
authors.lastname: Maciag
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Eddington
authors.forename: Vidya
authors.initials: V
authors.lastname: Udupi
authors.forename: Ken M
authors.initials: KM
authors.lastname: Kosak
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
mesh_terms: D001391:Azo Compounds / Q000494:pharmacology*; D020552:Comet Assay; D003561:Cytarabine / Q000494:pharmacology*; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*
chemical_list: 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; D003561:Cytarabine