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.
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Authors | Monika Z Kaczmarek, Ryan J Holland, Stephen A Lavanier, Jami A Troxler, Valentyna I Fesenkova, Charlotte A Hanson, Joan L Cmarik, Joseph E Saavedra, Larry K Keefer, Sandra K Ruscetti |
Journal | Leukemia research
(Leuk Res)
Vol. 38
Issue 3
Pg. 377-82
(Mar 2014)
ISSN: 1873-5835 [Electronic] England |
PMID | 24461365
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
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Copyright | Published by Elsevier Ltd. |
Chemical References |
- Azo Compounds
- Cytotoxins
- Forkhead Box Protein O3
- Forkhead Transcription Factors
- FoxO3 protein, mouse
- Nitric Oxide Donors
- O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate
- Phosphoinositide-3 Kinase Inhibitors
- Piperazines
- Prodrugs
- Proto-Oncogene Proteins c-akt
- Mitogen-Activated Protein Kinases
- Caspases
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Topics |
- Animals
- Azo Compounds
(pharmacology)
- Caspases
(genetics, metabolism)
- Cell Line, Tumor
- Cytotoxins
(pharmacology)
- Forkhead Box Protein O3
- Forkhead Transcription Factors
(agonists, genetics, metabolism)
- Gene Expression Regulation, Leukemic
(drug effects)
- Mice
- Mitogen-Activated Protein Kinases
(antagonists & inhibitors, genetics, metabolism)
- Nitric Oxide Donors
(pharmacology)
- Phosphatidylinositol 3-Kinases
(genetics, metabolism)
- Phosphoinositide-3 Kinase Inhibitors
- Piperazines
(pharmacology)
- Prodrugs
(pharmacology)
- Proto-Oncogene Proteins c-akt
(antagonists & inhibitors, genetics, metabolism)
- Signal Transduction
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