Abstract
Improved therapies are needed for nonsmall cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against nonsmall cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue and structural modification of these into more stable prodrugs. Compound 1 and its homopiperazine analogue 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 ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have antitumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Activating Transcription Factor 3 / biosynthesis
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Activating Transcription Factor 3 / genetics
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Activating Transcription Factor 3 / physiology*
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Apoptosis
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Cycle Checkpoints
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Cell Division
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Cell Line, Tumor
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Enzyme Activation
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G2 Phase
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Gene Silencing
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Humans
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JNK Mitogen-Activated Protein Kinases / physiology*
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Lung Neoplasms / drug therapy
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Lung Neoplasms / pathology
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Mice
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Mice, Nude
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Nitric Oxide Donors / chemical synthesis*
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Nitric Oxide Donors / chemistry
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Nitric Oxide Donors / pharmacology
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Piperazines / chemical synthesis
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Piperazines / chemistry
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Piperazines / pharmacology
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Prodrugs / chemical synthesis*
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Prodrugs / chemistry
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Prodrugs / pharmacology
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Signal Transduction
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Structure-Activity Relationship
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Up-Regulation
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Xenograft Model Antitumor Assays
Substances
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Activating Transcription Factor 3
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Antineoplastic Agents
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Nitric Oxide Donors
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Piperazines
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Prodrugs
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JNK Mitogen-Activated Protein Kinases