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

Overview

Journal J Pharm Pharmacol

Publisher Oxford University Press

Specialties Pharmacology
Pharmacy

Date 2013 Aug 10

PMID 23927471

Citations 6

Authors

Imit Kaur

Moises Terrazas

Ken M Kosak

Steven E Kern

Kenneth M Boucher

Paul J Shami

Affiliations

Soon will be listed here.

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 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.

Citing Articles

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A review of the relatively complex mechanism of JS-K induced apoptosis in cancer cells.

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Role of human glutathione transferases in biotransformation of the nitric oxide prodrug JS-K.

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Dong S, Sha H, Xu X, Hu T, Lou R, Li H Drug Des Devel Ther. 2018; 12:3535-3547.

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