Mechanism of action for the cytotoxic effects of the nitric oxide prodrug JS-K in murine erythroleukemia cells.
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.
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Monika Z
MZ
Kaczmarek
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Ryan J
RJ
Holland
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Stephen A
SA
Lavanier
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Jami A
JA
Troxler
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Valentyna I
VI
Fesenkova
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Charlotte A
CA
Hanson
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Joan L
JL
Cmarik
Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, MD, USA.
Joseph E
JE
Saavedra
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Larry K
LK
Keefer
Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA. Electronic address: ruscetts@mail.nih.gov.
Sandra K
SK
Ruscetti
D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D001391:Azo Compounds; D020169:Caspases; D003603:Cytotoxins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D020030:Nitric Oxide Donors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D011355:Prodrugs; D051057:Proto-Oncogene Proteins c-akt; C474033:FoxO3 protein, mouse; C474958:O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate
Apoptosis; FoxO3a; JS-K; Murine erythroleukemia cells