Cellular distribution studies of the nitric oxide‐generating antineoplastic prodrug O2‐(2, 4‐dinitrophenyl)1‐((4‐ethoxycarbonyl)piperazin‐1‐yl)diazen‐1‐ium‐1, 2‐diolate formulated in Pluronic P123 micelles. (10th July 2013)

• Record Type: Journal Article
• Authors: Kaur, Imit; Terrazas, Moises; Kosak, Ken M.; Kern, Steven E.; Boucher, Kenneth M.; Shami, Paul J.
• Is Part Of: Journal of pharmacy and pharmacology. Volume 65:Number 9(2013:Sep.)
• Page Start: 1329
• Page End: 1336
• Publication Date: 2013-07-10
• Subjects: Pharmacy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/jphp.12100
• Languages: English
• ISSNs: 0022-3573

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <sec id="jphp12100-sec-0001" sec-type="section"> <title>Objective</title> <p>Nitric oxide (NO) possesses antitumour activity. It induces differentiation and apoptosis in acute myeloid leukaemia (AML) cells. The NO prodrug <italic>O</italic><sup>2</sup>‐(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 <italic>in vitro</italic> and <italic>in vivo</italic> 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.</p> </sec> <sec id="jphp12100-sec-0002" sec-type="section"> <title>Methods</title> <p>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 <italic>S‐</italic>glutathionylating effects of JS‐K on proteins in the cytoplasmic and nuclear cellular fractions.</p> </sec> <sec id="jphp12100-sec-0003" sec-type="section"> <title>Key findings</title> <p>Both free JS‐K and P123/JS‐K accumulate primarily in the nucleus. Both free JS‐K and P123/JS‐K induced <italic>S</italic>‐glutathionylation of nuclear proteins, although the effect produced was more pronounced with P123/JS‐K. Minimal <italic>S‐</italic>glutathionylation of cytoplasmic proteins was observed.</p> </sec> <sec id="jphp12100-sec-0004" sec-type="section"> <title>Conclusions</title> <p>We conclude that a micelle formulation of JS‐K increases its accumulation in the nucleus. Post‐translational protein modification through <italic>S‐</italic>glutathionylation may contribute to JS‐K's antileukaemic properties.</p> </sec> </abstract>