In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2922-2922
Abstract:
JS-K is a nitric oxide (NO)-releasing drug of the O2-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models. It is activated for NO release by reaction with glutathione (GSH), a step that consumes an equivalent of GSH, effectively irreversibly. The two equivalents of NO thus released can be oxidized intracellularly, leading to S-nitrosylation and S-glutathionylation of GSH in a cascade of further reactions that consume additional equivalents of GSH and generate GSH disulfide (GSSG). The GSH/GSSG redox couple is the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. Here we show that depletion of GSH on treating U937 leukemia cells with JS-K markedly raises the reduction potential of the cell, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. The data indicate that multiplicative depletion of reduced GSH and deregulation of intracellular redox balance are important steps in the mechanism of JS-K's cytotoxic action. An additional GSH-consuming pathway was found to occur with Double JS-K, an aryl bis(diazeniumdiolate) created with the purpose of doubling the payload of NO. Double JS-K caused pronounced protein glutathionylation, in contrast to its monovalent counterpart. Serving as a bivalent electrophile, Double JS-K irreversibly crosslinked GSH to protein thiols through its aromatic linker. The results provide a previously unrecognized component of the multifaceted mechanism of action of bivalent electrophiles of the arylated diazeniumdiolate class. Citation Format: Ryan J. Holland, Anna E. Maciag, Robert Y.-S. Cheng, Luis G. Rodriguez, Joseph E. Saavedra, Lucy M. Anderson, Larry K. Keefer. Stoichiometric depletion of glutathione by anticancer agent JS-K. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2922. doi:10.1158/1538-7445.AM2013-2922
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-2922
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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