A new class of potent apogens (apoptosis-inducing agents) has been identified,consisting of 3-deazaadenosine (DZA), 3-deaza-( ± )aristeromycin (DZAri)and l-ß-D-arabinofuranosyl-lH-imidazo[4,5-c]pyridine (ara-3-deazaadenine;DZAra-A). They are inhibitors of S-adenosylhomocysteinc 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 G(2)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, whereas nur77 and GAPDH were unaffected. In comparison, there was an elevated expression of IFN-γ mRNA without apparent change in bax, p53 or GAPDH mRNA after 24 h. After treatment with DZA, there was an elevated expression of NF-(K)B 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.

Keywords:
Apoptosis, Cell cycle, 3-Deazaadenosine analogs, L1210 lymphocytic leukemia cells, c-myc, NF-kappa B
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1997
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