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

Leuk Res. 2014 Mar;38(3):377-82. doi: 10.1016/j.leukres.2013.12.002. Epub 2013 Dec 12.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Azo Compounds / pharmacology*
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cytotoxins / pharmacology*
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / agonists
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Leukemic / drug effects*
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitric Oxide Donors / pharmacology*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines / pharmacology*
  • Prodrugs / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction

Substances

  • 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