OBJECTIVE: Nitric oxide (NO) possesses antitumour activity. It induces differentiation and apoptosis in acute myeloid leukaemia (AML) cells. The NO prodrug O(2) -(2,4-dinitrophenyl)1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate, or JS-K, has potent antileukaemic activity. JS-K is also active in vitro and in vivo against multiple myeloma, prostate cancer, non-small-cell lung cancer, glioma and liver cancer. Using the Pluronic P123 polymer, we have developed a micelle formulation for JS-K to increase its solubility and stability. The goal of the current study was to investigate the cellular distribution of JS-K in AML cells. METHODS: We investigated the intracellular distribution of JS-K (free drug) and JS-K formulated in P123 micelles (P123/JS-K) using HL-60 AML cells. We also studied the S-glutathionylating effects of JS-K on proteins in the cytoplasmic and nuclear cellular fractions. KEY FINDINGS: Both free JS-K and P123/JS-K accumulate primarily in the nucleus. Both free JS-K and P123/JS-K induced S-glutathionylation of nuclear proteins, although the effect produced was more pronounced with P123/JS-K. Minimal S-glutathionylation of cytoplasmic proteins was observed. CONCLUSIONS: We conclude that a micelle formulation of JS-K increases its accumulation in the nucleus. Post-translational protein modification through S-glutathionylation may contribute to JS-K's antileukaemic properties.
OBJECTIVE:Nitric oxide (NO) possesses antitumour activity. It induces differentiation and apoptosis in acute myeloid leukaemia (AML) cells. The NO prodrug O(2) -(2,4-dinitrophenyl)1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate, or JS-K, has potent antileukaemic activity. JS-K is also active in vitro and in vivo against multiple myeloma, prostate cancer, non-small-cell lung cancer, glioma and liver cancer. Using the Pluronic P123 polymer, we have developed a micelle formulation for JS-K to increase its solubility and stability. The goal of the current study was to investigate the cellular distribution of JS-K in AML cells. METHODS: We investigated the intracellular distribution of JS-K (free drug) and JS-K formulated in P123 micelles (P123/JS-K) using HL-60AML cells. We also studied the S-glutathionylating effects of JS-K on proteins in the cytoplasmic and nuclear cellular fractions. KEY FINDINGS: Both free JS-K and P123/JS-K accumulate primarily in the nucleus. Both free JS-K and P123/JS-K induced S-glutathionylation of nuclear proteins, although the effect produced was more pronounced with P123/JS-K. Minimal S-glutathionylation of cytoplasmic proteins was observed. CONCLUSIONS: We conclude that a micelle formulation of JS-K increases its accumulation in the nucleus. Post-translational protein modification through S-glutathionylation may contribute to JS-K's antileukaemic properties.
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 Journal: Mol Cancer Ther Date: 2003-04 Impact factor: 6.261
Authors: Astrid Weyerbrock; Nadja Osterberg; Nikolaos Psarras; Brunhilde Baumer; Evangelos Kogias; Anna Werres; Stefanie Bette; Joseph E Saavedra; Larry K Keefer; Anna Papazoglou Journal: Neurosurgery Date: 2012-02 Impact factor: 4.654
Authors: Imit Kaur; Ken M Kosak; Moises Terrazas; James N Herron; Steven E Kern; Kenneth M Boucher; Paul J Shami Journal: Pharm Res Date: 2014-10-18 Impact factor: 4.200