Mechanism of action for the cytotoxic effects of the nitric oxide prodrug JS-K in murine erythroleukemia cells.

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.

• 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)
• 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

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