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 Pluronic P123 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 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.


RESULTS
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.
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, USA.
Imit
I
Kaur
Moises
M
Terrazas
Ken M
KM
Kosak
Steven E
SE
Kern
Kenneth M
KM
Boucher
Paul J
PJ
Shami
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D001391:Azo Compounds / Q000008:administration & dosage / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D004355:Drug Stability; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D008823:Micelles; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism*; D011060:Poloxalene / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational; D012995:Solubility
D000970:Antineoplastic Agents; D001391:Azo Compounds; D008823:Micelles; D020030:Nitric Oxide Donors; D009687:Nuclear Proteins; C474958:O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate; D010879:Piperazines; D011355:Prodrugs; C464484:pluronic block copolymer P123; D009569:Nitric Oxide; D011060:Poloxalene
JS-K; Pluronic; leukaemia; nitric oxide; poloxamer