PT  - JOURNAL ARTICLE
AU  - Anna E. Maciag
AU  - Harinath Chakrapani
AU  - Joseph E. Saavedra
AU  - Nicole L. Morris
AU  - Ryan J. Holland
AU  - Ken M. Kosak
AU  - Paul J. Shami
AU  - Lucy M. Anderson
AU  - Larry K. Keefer
TI  - The Nitric Oxide Prodrug JS-K is Effective Against Non-small Cell Lung Cancer Cells <em>in vitro</em> and <em>in vivo</em> : Involvement of Reactive Oxygen Species.
AID  - 10.1124/jpet.110.174904
DP  - 2010 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.110.174904
4099  - http://jpet.aspetjournals.org/content/early/2010/10/20/jpet.110.174904.short
4100  - http://jpet.aspetjournals.org/content/early/2010/10/20/jpet.110.174904.full
AB  - Non-small cell lung cancer is among the most common and deadly forms of human malignancies. Early detection is unusual and there are no curative therapies in most cases. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Here we show that O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) is a potent cytotoxic agent against a subset of human non-small cell lung cancer cell lines both in vitro and as xenografts in mice: JS-K treatment led to 75% reduction in the growth of H1703 lung adenocarcinoma cells in vivo. Differences in sensitivity to JS-K in different lung cancer cell lines appear to be related to their endogenous levels of reactive oxygen/nitrogen species (ROS/RNS). Other related factors, levels of peroxiredoxin 1 (PRX1) and 8-oxo-deoxyguanosine glycosylase (OGG1), also correlated with drug sensitivity. Treatment of the lung adenocarcinoma cells with JS-K resulted in oxidative/nitrosative stress in cells with high basal levels of ROS/RNS, 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. Taken together, the data suggest that diazeniumdiolate-based NO-releasing prodrugs may have application as a personalized therapy for lung cancers characterized by high levels of ROS/RNS. PRX1 and OGG1 proteins, which can be easily measured, could function as biomarkers for identifying tumors sensitive to the therapy.