ISSN:
1423-0127
Keywords:
Apoptosis
;
Cell cycle
;
3-Deazaadenosine analogs
;
L1210 lymphocytic leukemia cells
;
c-myc
;
NF-kappa B
Source:
Springer Online Journal Archives 1860-2000
Topics:
Biology
,
Medicine
Notes:
Abstract A new class of potent apogens (apoptosis-inducing agents) has been identified, consisting of 3-deazaadenosine (DZA), 3-deaza-(±)aristeromycin (DZAri) and 1-β-D-arabinofuranosyl-1H-imidazo[4,5-c]pyridine (ara-3-deazaadenine; DZAra-A). They are inhibitors ofS-adenosylhomocysteine hydrolase and indirect inhibitors of methylation. Furthermore, they have also been found to form 3-deaza-nucleotide analogs. The DZA analogs, DZA, DZAri, and DZAra-A, induced DNA fragmentation in a dose- and time-dependent manner, reaching a maximum at 250 µM after 72 h. Cycloheximide at 0.5 µg/ml completely blocked the DNA fragmentation induced by 250 µM of each of the analogs. Interestingly, exogenous 100 µM L-homocysteine thiolactone abrogated the DNA fragmentation caused by DZAri and DZAra-A, but not by DZA. Flow cytometric analysis showed that DZA arrested the cells in the G2/M phase, whereas the S phase was arrested by DZAri. Correlated with the effect of DZA was a rapid decrease in the expression of c-myc, whereasnur77 and GAPDH were unaffected. In comparison, there was an elevated expression of IFN-γ mRNA without apparent change inbax, p53 or GAPDH mRNA after 24 h. After treatment with DZA, there was an elevated expression of NF-κB DNA binding activity, which became more pronounced at 24 h. Simultaneously, there was an apparent disappearance of AP-1 activity. Thus, DZA most likely inhibited the RNA synthesis of c-myc, a reduction of which could trigger a cascade of gene transcription leading to apoptosis in L1210 cells.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF02255598
Permalink
