Cellular 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

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.