Selenium and the thioredoxin redox system: effects on cell growth and death.
Thioredoxin is a redox protein found overexpressed in some human tumors. Thioredoxin is secreted by tumor cells and enhances the sensitivity of the cancer cells to other growth factors. Redox activity is essential for stimulation of cell growth by thioredoxin. Cells transfected with thioredoxin cDNA show increased tumor growth and decreased apoptosis in vivo and decreased sensitivity to apoptosis induced by a variety of agents both in vitro and in vivo. Cells transfected with a redox-inactive mutant thioredoxin show inhibited tumor growth in vivo. Dietary selenium has been shown to prevent some forms of human cancer. Selenocysteine is an essential component of thioredoxin reductase, the flavoenzyme that is responsible for the reduction of thioredoxin. Selenium added to the culture medium increases thioredoxin reductase activity due to an increase in thioredoxin reductase protein but mostly due to an increase in the specific activity of the enzyme. Some diaryl chalcogenide (selenium and tellurium) compounds have been studied as inhibitors of thioredoxin reductase. The most active were diaryl tellurium compounds, which were noncompetitive inhibitors of thioredoxin reductase with Ki values of 2-10 microM. Several of the compounds inhibited cancer cell colony formation in vitro with IC50s as low as 2 microM.
Powis
G
G
Arizona Cancer Center, University of Arizona, Tucson 85724-5024, USA. gpowis@azcc.arizona.edu
Gasdaska
J R
JR
Gasdaska
P Y
PY
Berggren
M
M
Kirkpatrick
D L
DL
Engman
L
L
Cotgreave
I A
IA
Angulo
M
M
Baker
A
A
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D006801:Humans; D010084:Oxidation-Reduction; D012643:Selenium / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*
D013879:Thioredoxins; D013880:Thioredoxin-Disulfide Reductase; D012643:Selenium