Abstract
The nitric oxide (NO) prodrug JS-K, a promising anti-cancer agent, consists of a diazeniumdiolate group necessary for the release of NO as well as an arylating ring. In this study, we research the mechanism by which JS-K kills a murine erythroleukemia cell line and determine the roles of NO and arylation in the process. Our studies indicate that JS-K inhibits the PI 3-kinase/Akt and MAP kinase pathways. This correlates with the activation of the tumor suppressor FoxO3a and increased expression of various caspases, leading to apoptosis. The arylating capability of JS-K appears to be sufficient for inducing these biological effects. Overall, these data suggest that JS-K kills tumor cells by arylating and inactivating signaling molecules that block the activation of a tumor suppressor.
Keywords:
Apoptosis; FoxO3a; JS-K; Murine erythroleukemia cells.
Published by Elsevier Ltd.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Azo Compounds / pharmacology*
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Caspases / genetics
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Caspases / metabolism
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Cell Line, Tumor
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Cytotoxins / pharmacology*
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Forkhead Box Protein O3
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Forkhead Transcription Factors / agonists
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation, Leukemic / drug effects*
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Mice
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Nitric Oxide Donors / pharmacology*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines / pharmacology*
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Prodrugs / pharmacology*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
Substances
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Azo Compounds
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Cytotoxins
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Nitric Oxide Donors
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O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines
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Prodrugs
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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Caspases