In:
Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. C175-C175
Abstract:
Non-small cell lung cancer (NSCLC) is among the most common and deadly forms of human malignancies. Early detection is unusual and cures are limited to early stage disease. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. O2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) is a potent anticancer agent that has proven effective in several cancer models in vitro and in vivo, including NSCLC. Here we report mechanistic studies with JS-K and its homopiperazine analogue and structural modification of these into more stable prodrugs. Prodrugs of the JS-K class were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector, activating transcription factor 3 (ATF3). Treatment of the NSCLC cells with JS-K resulted in oxidative/nitrosative stress, which combined with the arylating properties of the compound was reflected in glutathione depletion and alteration in cellular redox potential, mitochondrial membrane permeabilization and cytochrome c release. Inactivation of MnSOD by nitration was associated with increased superoxide and significant DNA damage. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have anti-tumor activity. The data suggest that: 1) diazeniumdiolate-based NO-releasing prodrugs may have application as a therapy for lung cancer; 2) rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C175.
Type of Medium:
Online Resource
ISSN:
1535-7163
,
1538-8514
DOI:
10.1158/1535-7163.TARG-11-C175
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2062135-8
SSG:
12
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