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- W2010239217 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." @default.
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- W2010239217 date "2011-11-12" @default.
- W2010239217 modified "2023-09-25" @default.
- W2010239217 title "Abstract C175: JS-K, a nitric oxide-releasing anticancer prodrug with a broad spectrum of action." @default.
- W2010239217 doi "https://doi.org/10.1158/1535-7163.targ-11-c175" @default.
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