Oxidative stress and inhibition of nitric oxide generation underlie methotrexate-induced senescence in human colon cancer cells.
Mech Ageing Dev
; 170: 22-29, 2018 03.
Article
in En
| MEDLINE
| ID: mdl-28739375
ABSTRACT
The response of human colon cancer C85 cells to methotrexate takes the form of reversible growth arrest of the type of stress-induced senescence. In the present study it is shown that during C85 cell progression into methotrexate-induced senescence, dihydrofolate reductase, the primary intracellular target for the drug, is stabilized at the protein level and its enzymatic activity, assayed in crude cellular extracts, decreases by 2-fold. Dihydrofolate reductase inhibition results in an increase in dihydrobiopterin level and an ultimate decrease in the tetrahydrobiopterin dihydrobiopterin ratio in senescent cells. Endothelial nitric oxide synthase expression declines. Despite concomitant upregulation of inducible nitric oxide synthase expression, no nitric oxide generation in senescent cells is detected. Progressing oxidative stress accompanies establishment of the state of senescence. DNA damage, in the form of double strand-breaks, occurs at the highest level at the senescence initiation phase and decreases as cells progress into the senescence maintenance phase.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Methotrexate
/
Cellular Senescence
/
Colonic Neoplasms
/
Oxidative Stress
Limits:
Humans
Language:
En
Journal:
Mech Ageing Dev
Year:
2018
Type:
Article