The effect of JS-K, a lead O2-arylated diazeniumdiolate anti-cancer agent, on the cellular glutathione status

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NCI	BIOCHEM/CHEM-9

Authors

• RJ Holland
• AE Maciag
• LG Rodriguez
• JE Saavedra
• LK Keefer

Abstract

JSK is an O2-arylated diazeniumdiolate prodrug which has demonstrated pronounced cytotoxicity and antitumorigenic properties in a variety of cancer models both in vitro and in vivo. A study of the metabolic fate of JS-K was undertaken to understand the origin of the cytotoxicity. Consistent with model chemical reactions, the first step in the metabolism of JS-K in cultured U937 leukemia cells is the de-arylation of the diazeniumdiolate by glutathione (GSH) via nucleophilic aromatic substitution reaction, ultimately releasing nitric oxide (NO). A consequence of this metabolism and subsequent NO-generation is a rapid and pronounced depletion of cellular GSH concurrent with a rise in oxidized glutathione (GSSG). The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. The depletion of GSH, through drug conjugation and oxidation, results in a rise in the oxidation potential of the cellular environment, initiating stress signaling pathways which lead to extrinsic apoptosis. Preventing this rise in the oxidation potential by pre-treating cells with known antioxidant N-acetylcysteine inhibited the downstream signaling events leading to apoptosis. These data indicate that depletion of the glutathione pool is a crucial first step in the mechanism of JS-K cytotoxicity.

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