Open AccessCellular distribution studies of the nitric oxide‐generating antineoplastic prodrug O 2 ‐(2,4‐dinitrophenyl)1‐((4‐ethoxycarbonyl)piperazin‐1‐yl)diazen‐1‐ium‐1,2‐diolate formulated in P luronic P 123 micelles
Author(s) -
Kaur Imit,
Terrazas Moises,
Kosak Ken M.,
Kern Steven E.,
Boucher Kenneth M.,
Shami Paul J.
Publication year - 2013
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/jphp.12100
Subject(s) - poloxamer , micelle , nitric oxide , chemistry , prodrug , in vivo , dinitrophenyl , cancer research , biochemistry , medicine , biology , copolymer , immunology , organic chemistry , polymer , microbiology and biotechnology , aqueous solution , antibody
Abstract 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 P luronic P 123 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 P 123 micelles ( P 123/ 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 P 123/ JS ‐ K accumulate primarily in the nucleus. Both free JS ‐ K and P 123/ JS ‐ K induced S ‐glutathionylation of nuclear proteins, although the effect produced was more pronounced with P 123/ 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.